Tri-substituted phenyl derivatives and processes for their preparation

ABSTRACT

Compounds of general formula (1) are described:  
                 
 
     wherein  
     ═W— is (1) ═C(Y)— where Y is a halogen atom, or an alkyl or —XR a  group where X is —O—, —S(O) m —[where m is zero or an integer of value 1 or 2], or —N(R b )—[where R b  is a hydrogen atom or an optionally substituted alkyl group] and R a  is a hydrogen atom or an optionally substituted alkyl group or, (2) ═N—;  
     L is (1) a —C(R)═C(R 1 )(R 2 ) or [—CH(R)] n CH(R 1 )(R 2 ) group; is (2) a —(X a ) n Alk′Ar′, or Alk′X a Ar′ group; or is (3) X a R 1 ;  
     Z is a group (A), (B), (C) or (D):  
                 
 
     wherein  
     Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms;  
     Z 1  is a group —NR 12 C(O)—[where R 12  is a hydrogen atom or an optionally substituted alkyl or (Alk) t Ar group], —C(O)NR 12 —, —NR 12 C(S)—, —C(S)NR 12 —, —C≡C—, —NR 12 SO 2 —, or —SO 2 NR 12 —;  
     Alk is an optionally substituted straight or branched alkyl chain optionally interrupted by an atom or group X;  
     t is zero or an integer of value 1, 2 or 3;  
     R 3  is a hydrogen or a fluorine atom or an optionally substituted straight or branched alkyl group or an OR 11  group [where R 11  is a hydrogen atom or an optionally substituted alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group];  
     R 4  is a hydrogen atom or an optionally substituted alkyl, —CO 2 R 8 , —CSNR 9 R 10 , —CN, —CH 2 CN, or —(CH 2 ) t Ar group where t is zero or an integer of value 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms; provided that when L is a group of type (2) or (3) above then Z is a group of type (A) or type (B) in which R 4  is a —(CH 2 ) t Ar group;  
     R 5  is a group —(CH 2 ) t Ar;  
     R 6  is a hydrogen or a fluorine atom, or an optionally substituted alkyl or —CO 2 R 8 , —CONR 9 R 10 , —CSNR 9 R 10 , —CN or —CH 2 CN group;  
     R 7  is a hydrogen or a fluorine atom, an optionally substituted straight or branched alkyl group, or an OR c  group where R c  is a hydrogen atom or an optionally substituted alkyl or alkenyl group, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group; and the salts, solvates, hydrates, prodrugs and N-oxides thereof.  
     Compounds according to the invention are phosphodiesterase type IV inhibitors and are useful in the prophylaxis and treatment of disease such as asthma where unwanted inflammatory response or muscular spasm is present.

[0001] This invention relates to a novel series of tri-substitutedphenyl derivatives, to processes for their preparation, topharmaceutical compositions containing them, and to their use inmedicine.

[0002] Many hormones and neurotransmitters modulate tissue function byelevating intra-cellular levels of adenosine 3′, 5′-cyclic monophosphate(cAMP). The cellular levels of cAMP are regulated by mechanisms whichcontrol synthesis and breakdown. The synthesis of cAMP is controlled byadenyl cyclase which may be directly activated by agents such asforskolin or indirectly activated by the binding of specific agonists tocell surface receptors which are coupled to adenyl cyclase. Thebreakdown of cAMP is controlled by a family of phosphodiesterase (PDE)isoenzymes, which also control the breakdown of guanosine 3′,5′-cyclicmonophosphate (cGMP). To date, seven members of the family have beendescribed (PDE I-VII) the distribution of which varies from tissue totissue. This suggests that specific inhibitors of PDE isoenzymes couldachieve differential elevation of cAMP in different tissues, [forreviews of PDE distribution, structure, function and regulation, seeBeavo & Reifsnyder (1990) TIPS, 11: 150-155 and Nicholson et al (1991)TIPS, 12: 19-27].

[0003] There is clear evidence that elevation of cAMP in inflammatoryleukocytes leads to inhibition of their activation. Furthermore,elevation of cAMP in airway smooth muscle has a spasmolytic effect. Inthese tissues, PDE IV plays a major role in the hydrolysis of cAMP. Itcan be expected, therefore, that selective inhibitors of PDE IV wouldhave therapeutic effects in inflammatory diseases such as asthma, byachieving both anti-inflammatory and bronchodilator effects.

[0004] The design of PDE IV inhibitors has met with limited success todate, in that many of the potential PDE IV inhibitors which have beensynthesised have lacked potency and/or have been capable of inhibitingmore than one type of PDE isoenzyme in a non-selective manner. Lack of aselective action has been a particular problem given the widespread roleof cAMP in viva and what is needed are potent selective PDE IVinhibitors with an inhibitory action against PDE IV and little or noaction against other PDE isoenzymes.

[0005] We have now found a novel series of tri-substituted phenylderivatives, members of which are potent inhibitors of PDE IV atconcentrations at which they have little or no inhibitory action onother PDE isoenzymes. These compounds inhibit the human recombinant PDEIV enzyme and also elevate cAMP in isolated leukocytes. The compounds ofthe invention are therefore of use in medicine, especially in theprophylaxis and treatment of asthma.

[0006] Thus according to one aspect of the invention, we provide acompound of formula (1)

[0007] wherein

[0008] ═W— is (1) ═C(Y)— where Y is a halogen atom, or an alkyl or—XR^(a) group where X is —O—, —S(O)_(m)—[where m is zero or an integerof value 1 or 2], or —N(R^(b))—[where R^(b) is a hydrogen atom or anoptionally substituted alkyl group] and R^(a) is a hydrogen atom or anoptionally substituted alkyl group or, (2) ═N—;

[0009] L is (1) a —C(R)═C(R¹)(R²) or [—CH(R)]_(n)CH(R¹)(R²) group whereR is a hydrogen or a fluorine atom or a methyl group, and R¹ and R²,which may be the same or different, is each a hydrogen or fluorine atomor an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio,—CO₂R⁸ [where R⁸ is a hydrogen atom or an optionally substituted alkyl,aralkyl or aryl group], —CONR⁹R¹⁰ [where R⁹ and R¹⁰, which may be thesame or different are defined for R⁸], —CSNR⁹R¹⁰,—CN or —NO₂ group, orR¹ and R², together with the C atom to which they are attached arelinked to form an optionally substituted cycloalkyl, cycloalkenyl orheterocycloaliphatic group and n is zero or the integer 1; or is(2)—(X^(a))_(n)Alk′Ar′, or -Alk′X^(a)Ar′ where X^(a) is a group X, Ar′is an optionally substituted heterocycloaliphatic, or an optionallysubstituted monocylic or bicyclic aryl group optionally containing oneor more heteroatoms selected from oxygen, sulphur or nitrogen atoms,Alk′ is an optionally substituted straight or branched alkylene,alkenylene or alkynylene chain optionally interrupted by one or more L¹atoms or groups [where L¹ is a linker atom or group] and n is zero orthe integer 1; or is (3) X^(a)R′ where R′ is Ar′ or is an optionallysubstituted polycycloalkyl or polycycloalkenyl group optionallycontaining one or more —O—, or —S— atoms or —N(R^(b))— groups;

[0010] Z is a group (A), (B), (C) or (D):

[0011] wherein

[0012] Ar is a monocyclic or bicyclic aryl group optionally containingone or more heteroatoms selected from oxygen, sulphur or nitrogen atoms;

[0013] Z¹ is a group —NR¹²C(O)—[where R¹² is a hydrogen atom or anoptionally substituted alkyl or (Alk)_(t)Ar group], —C(O)NR¹²—,—NR¹²C(S)—, —C(S)NR¹²—, —C≡C—, —NR¹²SO₂—, or —SO₂NR¹²—;

[0014] Alk is an optionally substituted straight or branched alkyl chainoptionally interrupted by an atom or group X;

[0015] t is zero or an integer of value 1, 2 or 3;

[0016] R³ is a hydrogen or a fluorine atom or an optionally substitutedstraight or branched alkyl group or an OR¹¹ group [where R¹¹ is ahydrogen atom or an optionally substituted alkyl, alkenyl, alkoxyalkyl,alkanoyl, formyl, carboxamido or thiocarboxamido group];

[0017] R⁴ is a hydrogen atom or an optionally substituted alkyl, —CO₂R⁸,—CSNR⁹R¹⁰, —CN, —CH₂CN, or —(CH₂)_(t)Ar group where t is zero or aninteger of value 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl groupoptionally containing one or more heteroatoms selected from oxygen,sulphur or nitrogen atoms, provided that when L is a group of type (2)or (3) above then Z is a group of type (A) or type (B) in which R⁴ is a—(CH₂)_(t)Ar group;

[0018] R⁵ is a group —(CH₂)_(t)Ar;

[0019] R⁶ is a hydrogen or a fluorine atom, or an optionally substitutedalkyl or —CO₂R⁸, —CONR⁹R¹⁰, —CSNR⁹R¹⁰, —CN or —CH₂CN group;

[0020] R⁷ is a hydrogen or a fluorine atom, an optionally substitutedstraight or branched alkyl group, or an OR^(c) group where R^(c) is ahydrogen atom or an optionally substituted alkyl or alkenyl group,alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group; andthe salts, solvates, hydrates, prodrugs and N-oxides thereof.

[0021] It will be appreciated that certain compounds of formula (1) mayhave one or more chiral centres, depending on the nature of the groupsAlk, R¹, R², R³ R⁴, R⁵, R⁶ and R⁷. Where one or more chiral centres ispresent, enantiomers or diastereomers may exist, and the invention is tobe understood to extend to all such enantiomers, diastereomers andmixtures thereof, including racemates.

[0022] Compounds of formula (1) in which L is a —C(R)═C(R¹)(R²) groupand/or Z is the group (B), may exist as geometric isomers depending onthe nature of the groups R, R¹, R², R⁴, R⁵ and R⁶, and the invention isto be understood to extend to all such isomers and mixtures thereof.

[0023] In the compounds of formula (1), when ═W— is ═C(Y)— and Y is ahalogen atom Y may be for example a fluorine, chlorine, bromine oriodine atom.

[0024] When W in the compounds of formula (1) is a group ═C(Y)— and Y is—XR^(a), R^(a) may be, for example, a hydrogen atom or an optionallysubstituted straight or branched alkyl group, for example, an optionallysubstituted C₁₋₆alkyl group, such as a methyl, ethyl, n-propyl or1-propyl group. Optional substituents which may be present on R^(a)groups include one or more halogen atoms, e.g. fluorine, or chlorineatoms. Particular R^(a) groups include for example —CH₂F, —CH₂Cl, —CHF₂,—CHCl₂, —CF₃ or —CCl₃ groups.

[0025] When ═W— in the compounds of formula (1) is a group ═C(Y)— where—Y is —N(R^(b)), ═W— may be a ═C(NH₂)—, ═C(NHCH₃)— or ═C(NHC₂H₅)— group.

[0026] In compounds of formula (1), X may be an oxygen or a sulphuratom, or a group —S(O)—, —S(O)₂—, —NH— or C₁₋₆ alkylamino, for example aC₁₋₃ alkylamino, e.g. methylamino [—N(CH₃)—] or ethylamino [—N(C₂H₅)-]group.

[0027] Alkyl groups represented by Y, R¹, R² or R^(b) in the compoundsof formula (1) include optionally substituted straight or branched C₁₋₆alkyl groups optionally interrupted by one or more X atoms or groups.Particular examples include C₁₋₃ alkyl groups such as methyl, ethyl,n-propyl or i-propyl groups. Optional substituents on these groupsinclude one, two or three substituents selected from halogen atoms, e.g.fluorine, chlorine, bromine or iodine atoms, or hydroxyl or C₁₋₆ alkoxye.g. C₁₋₃ alkoxy such as methoxy or ethoxy or —CO₂R⁸, —CONR⁹R¹⁰,—CSNR⁹R¹l or —CN groups. Particular substituted alkyl groups include forexample —CH₂F, —CH₂Cl, —CHF₂, CHCl₂, —CH₃ or —CCl₃ groups.

[0028] Alkenyl groups represented by R¹ or R² in the compounds offormula (1) include optionally substituted straight or branchedC₂₋₆alkenyl groups optionally interrupted by one or more X atoms orgroups. Particular examples include ethenyl, propen-1-yl and2-methylpropen-1-yl groups. Optional substituents include thosedescribed above in relation to alkyl groups represented by the groups R¹or R².

[0029] Alkynyl groups represented by R¹ or R² in compounds of formula(1) include optionally substituted straight or branched C₂₋₆alkynylgroups optionally interrupted by one or more X atoms or groups.Particular examples include ethynyl and propyn-1-yl groups. Optionalsubstituents include those described above in relation to alkyl groupsrepresented by the groups R¹ or R².

[0030] When R¹ or R² in compounds of formula (1) is an alkoxy oralkylthio group it may be for example an optionally substitutedC₁₋₆alkoxy or C₁₋₆alkylthio group optionally interrupted by one or moreX atoms or groups. Particular examples include C₁₋₃alkoxy, e.g. methoxyor ethoxy, or C₁₋₃alkylthio e.g. methylthio or ethylthio groups.Optional substituents include those described above in relation to alkylgroups represented by the groups R¹ or R².

[0031] When R¹ and R² together with the carbon atom to which they areattached in the compounds of formula (1) are linked to form a cycloalkylor cycloalkenyl group, the group may be for example a C₃₋₈cycloalkylgroup such as a cyclobutyl, cyclopentyl or cyclohexyl group or a C₃₋₈cycloalkenyl group containing for example one or two double bonds suchas a 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,2,4-cyclopentadien-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,2,4-cyclohexadien-1-yl or 3,5-cyclohexadien-1-yl group, each cycloalkylor cycloalkenyl group being optionally substituted by one, two or threesubstituents selected from halogen atoms, e.g. fluorine, chlorine,bromine or iodine atoms, straight or branched C₁₋₆alkyl e.g. C₁₋₃alkylsuch as methyl or ethyl, hydroxyl or C₁₋₆alkoxy e.g. C₁₋₃alkoxy such asmethoxy or ethoxy groups. The linker atoms represented by the group L¹include for example —O— or —S— atoms. Particular groups represented bythe linker group L¹ are —S(O)—, —S(O)₂—, —N(R^(b))—, —C(O)—, —C(O)₂—,—C(S)—, —C(NR^(b))— —CON(R^(b))—, —CSN(R^(b))—, —N(R^(b))CO—,—N(R^(b))CS—, —SON(R^(b))—, —S₂N(R^(b))—, N(R^(b))SO-, —N(R^(b))SO₂—,N(R^(b))SO₂N(R^(b))—, —N(R^(b))SON(R^(b))—, —N(R^(b))CON(R^(b))— or—N(R^(b))CSN(R^(b))— groups. It will be appreciated that when the chainAlk is interrupted by two or more L¹ atoms or groups, such atoms orgroups may be adjacent to one another, for example to form a group—N(R^(b))—C(NR^(b))—N(R^(b))— or —O—CONH—.

[0032] When L is a —(X^(a))_(n)Alk′Ar′ or Alk′X^(a)Ar′ group where Alk′is an alkylene chain L may be for example an optionally substitutedstraight or branched C₁₋₈alkylene chain optionally interrupted by one ormore L¹ linker atoms or groups. Particular examples include —CH₂Ar′,—(CH₂)₂Ar′, —OAr′, —SAr′, —N(R^(b))Ar′, —C(O)Ar′, —C(S)Ar′,—CON(R^(b))Ar′, —CSN (R^(b))Ar′, —SOAr′, —SON(R^(b))Ar′, —SO₂Ar′,—SO₂N(R^(b))Ar′, OCH₂Ar′, —SCH₂Ar′, —N(R^(b))CH₂Ar′, —CH₂OAr′, —CH₂SAr′,—CH₂N(R^(b))Ar′, —CH₂C(O)Ar′, —CH₂C(S)Ar′, —CH₂CON(R^(b))Ar′,—CH₂CSN(R^(b))Ar′, —CH₂SOAr′, —CH₂ SO₂Ar′, —(CH₂)₂OCH₂Ar′,—(CH₂)₂SCH₂Ar′, —(CH₂)₂SOCH₂Ar′, —(CH₂)₂SO₂CH₂Ar′, —(CH₂)₃Ar′,—O(CH₂)₃Ar′, —S(CH₂)₃Ar′, —N(R^(b))(CH₂)₃Ar′, —SO(CH₂)₃Ar′,—SO₂(CH₂)₃Ar′, —(CH₂)₃OAr′, —(CH₂)₃SAr′, —(CH₂)₃N(R^(b))Ar′,—(CH₂)₃SOAr′ or —(CH₂)₃SO₂Ar′ group. Optional substituents on thesegroups include those mentioned above in relation to the alkyl groupsrepresented by Y, R¹, R² or R^(b).

[0033] When L is a —(X^(a))_(n)Alk′Ar′ or Alk′X^(a)Ar′ group where Alk′is an alkenylene chain it may be an optionally substituted straight orbranched mono or polyunsaturated C₂₋₈alkenylene chain optionallyinterrupted by one or more L¹ linker atoms or groups. Particularexamples include —(CH═CH)Ar′, —CH═CH—CH₂Ar′, —CH₂—CH═CHAr′,—CH═CH—CH₂Ar′, —CH₂—CH═CHAr′, —OCH═CH—CH₂Ar′, —OCH₂—CH═CHAr′,—SCH═CH—CH₂Ar′, —SCH₂—CH═CHAr′, —N(R^(b))CH═CH—CH₂Ar′, —CH═CH—CH₂—OAr′,—CH₂—CH═CH₂—OAr′ or —CH═CH—CH═CHAr′ group. Optional substituents onthese groups include those mentioned above in relation to the alkylgroups represented by Y, R¹, R² or R^(b).

[0034] When L is a (X^(a))_(n)Alk′Ar′ or Alk′X^(a)Ar′ group where Alk′is an alkynylene chain, it may be an optionally substituted straight orbranched mono or polyunsaturated C₂₋₈alkynylene chain optionallyinterrupted by one or more L¹ linker atoms or groups. Particularexamples include —C≡CAr′, —C≡C—CH₂Ar′, —CH₂—C≡C—Ar′, —OC—C—CH₂Ar′,—OCH₂—C≡CAr′, —SC≡C—CH₂Ar′, —SCH₂—C≡CAr′, —N(R^(b))C≡C—CH₂Ar′,—N(R^(b))CH₂—C≡CAr′, —C≡C—CH₂OAr′, —CH₂—C≡COAr′, —C≡C—CH₂SAr′,—CH₂—C=—CSAr′, —CH₂—C≡CN(R^(b))Ar′ or C=—C—CH₂N(R^(b))Ar′ group.Optional substituents on these groups include those mentioned above inrelation to the alkyl groups represented by Y, R¹, R² or R^(b).

[0035] When R¹ and R², together with the C atom to which they areattached are linked to form an optionally substitutedheterocycloaliphatic group, and/or when Ar′ is a heterocycloaliphaticgroup, the group may be for example an optionally substituted C₃₋₈cycloalkyl or C₃₋₈ cycloalkenyl group containing one or more —O—, or —S—atoms, or —N(R^(b))— groups such as a pyrrolidinyl, dioxolanyl, e.g.1,3-dioxolanyl, imidazolidinyl, pyrazolidinyl, piperidinyl,1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl,1,3,5-trithianyl, 3-pyrrolinyl, 2-imidazolinyl, or 2-pyrazolinyl group.Optional substituents which may be present on such groups include one,two or three substituents selected from halogen atoms, e.g. fluorine,chlorine, bromine or iodine atoms, straight or branched C₁₋₆ alkyl e.g.C₁₋₃ alkyl such as methyl or ethyl, hydroxyl or C₁₋₆ alkoxy e.g. C₁₋₃alkoxy such as methoxy or ethoxy groups.

[0036] Polycycloalkyl groups represented by R′ in compounds of formula(1) include optionally substituted C6-10 polycycloalkyl, e.g.bicycloalkyl or tricycloalkyl groups optionally containing one, two ormore —O— or —S— atoms or —N(R^(b))— groups. Polycycloalkenyl groupsrepresented by Ar′ include optionally substituted C₆₋₁₀polycycloalkenyl, e.g. bicycloalkenyl or tricycloalkenyl groupsoptionally containing one, two or more —O— or —S— atoms or —N(R^(b))groups. The degree of unsaturation of polycycloalkenyl groups may bevaried widely and the term is to be understood to include groups withone, two, three or more —CH═CH— groups. Optional substituents which maybe present on such groups include those mentioned above in relation tothe Ar′ group when Ar′ is a heterocycloaliphatic group.

[0037] When the group R⁷ in compounds of formula (1) is an OR^(c) groupit may be for example a hydroxyl group; or a group —OR^(c) where R^(c)is an optionally substituted straight or branched C₁₋₆alkyl group, e.g.a C₁₋₃alkyl group such as a methyl or ethyl group, a C₂₋₆alkenyl groupsuch as an ethenyl or 2-propen-1-yl group, a C₁₋₃alkoxyC₁₋₃alkyl groupsuch as a methoxymethyl, ethoxymethyl or ethoxyethyl group, aC₁₋₆alkanoyl, e.g. C₁₋₃alkanoyl group such as an acetyl group, or aformyl [HC(O)—], carboxamido (CONR¹³R^(13a)) or thiocarboxamido(CSNR¹3R^(13a)) group, where R¹³ and R^(13a) in each instance may be thesame or different and is each a hydrogen atom or an optionallysubstituted straight or branched C₁₋₆alkyl, e.g. C₁₋₃alkyl group such asmethyl or ethyl group. Optional substituents which may be present onsuch R^(c), R¹³ or R^(13a) groups include those described below inrelation to the alkyl groups R³, R⁴, R⁶, R⁷ and R¹².

[0038] Alkyl groups represented by R³, R⁴, R⁶, R⁷ or R¹² in compounds offormula (1) include optionally substituted straight or branched C₁₋₆alkyl groups, e.g. C₁₋₃ alkyl groups such as methyl, ethyl, n-propyl or1-propyl groups. Optional substituents which may be present on thesegroups include one or more halogen atoms, e.g. fluorine, chlorine,bromine or iodine atoms, or hydroxyl or C₁₋₆alkoxy e.g. C₁₋₃alkoxy suchas methoxy or ethoxy groups.

[0039] When R¹, R², R⁴ or R⁶ is a —CO₂R⁸, —CONR⁹R¹⁰ or CSNR⁹R¹⁰ group itmay be for example a —CO₂H, —CONH₂ or —CSNH₂ group or a group —CO₂R⁸,—CONR⁹R¹⁰, —CSNR⁹R¹⁰, —CONHR¹⁰, or —CSNHR¹⁰ where R⁸, R⁹ and R¹⁰ wherepresent is a C₁₋₃alkyl group such as methyl or ethyl group, a C₆₋₁₂arylgroup, for example an optionally substituted phenyl, or a 1— or 2—naphthyl group, or a C₆₋₁₂aryl C₁₋₃alkyl group such as an optionallysubstituted benzyl or phenethyl group. Optional substituents which maybe present on these aryl groups include R¹⁴ substituents discussed belowin relation to the group Ar.

[0040] When the chain Alk is present in compounds of formula (1) it maybe an optionally subtituted straight or branched C₁₋₃alkylene chainoptionally interrupted by an atom or group X. Particular examplesinclude —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —CH₂OCH₂—, —CH₂SCH₂—, or—CH₂N(R^(b))CH₂, e.g. —CH₂NHCH₂— or —CH₂N(CH₃)CH₂— chains. Optionalsubstituents include those described in relation to the alkyl groupsrepresented by R³, R⁴, R⁶, R⁷ and R¹²

[0041] In the compounds of formula (1) when the group—(Alk)_(t)(X)_(n)Ar is present it may be a group —Ar, —CH₂Ar, —(CH₂)2Ar,—(CH₂)₃Ar, —CH₂OAr, —CH₂OCH₂Ar, —CH₂N(R^(b))Ar or —CH₂N(R^(b))CH₂Argroup.

[0042] Monocyclic or bicyclic aryl groups represented by the group Ar,Ar′, or R′ in compounds of formula (1) include for example C₆₋₁₂optionally substituted aryl groups, for example optionally substitutedphenyl, 1-or 2-naphthyl, indenyl or isoindenyl groups.

[0043] When the monocyclic or bicyclic aryl group Ar, Ar′ or R′ containsone or more heteroatoms it may be for example a C₅₋₁₀ optionallysubstituted heteroaryl group containing for example one, two, three orfour heteroatoms selected from oxygen, sulphur or nitrogen atoms. Ingeneral, Ar heteroaryl groups may be for example monocyclic or bicyclicheteroaryl groups. Monocyclic heteroaryl groups include for examplefive- or six-membered heteroaryl groups containing one, two, three orfour heteroatoms selected from oxygen, sulphur or nitrogen atoms.Bicyclic heteroaryl groups include for example nine- or ten-memberedheteroaryl groups containing one, two or more heteroatoms selected fromoxygen, sulphur or nitrogen atoms.

[0044] Examples of heteroaryl groups represented by Ar, Ar′ or R′include pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl,N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl,isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl,benzoxazolyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl,pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl,tetrazolyl, 5,6,7,8-tetrahydroquinolinyl and5,6,7,8-tetrahydroisoquinolinyl. Example of bicyclic heteroaryl groupsinclude quinolinyl or isoquinolinyl groups.

[0045] The heteroaryl group represented by Ar, Ar′ or R′ may be attachedto the remainder of the molecule of formula (1) through any ring carbonor heteroatom as appropriate. Thus, for example, when the group Ar orAr′ is a pyridyl group it may be a 2-pyridyl, 3-pyridyl or 4-pyridylgroup. When it is a thienyl group it may be a 2-thienyl or 3-thienylgroup, and, similarly, when it is a furyl group it may be a 2-furyl or3-furyl group. In another example, when the group Ar is a quinolinylgroup it may be a 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl and when it isan isoquinolinyl, it may be a 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinylgroup.

[0046] When in compounds of formula (1) the Ar, Ar′ or R′ group is anitrogen-containing heterocycle it may be possible to form quaternarysalts, for example N-alkyl quaternary salts and the invention is to beunderstood to extend to such salts. Thus for example when the group Aris a pyridyl group, pyridinium salts may be formed, for exampleN-alkylpyridinium salts such as N-methylpyridinium.

[0047] The aryl or heteroaryl groups represented by Ar, Ar′ or R′, incompounds of formula (1) may each optionally be substituted by one, two,three or more substituents [R¹⁴]. The substituent R¹⁴ may be selectedfrom an atom or group R¹⁵ or -Alk¹(R¹⁵)_(m) wherein R¹⁵ is a halogenatom, or an amino (—NH₂), substituted amino, nitro, cyano, hydroxyl(—OH), substituted hydroxyl, cycloalkoxy, cycloaliphatic, formyl[HC(O)—], carboxyl (—CO₂H), esterified carboxyl, thiol (—SH),substituted thiol, —C(O)R″ [where R″ is a group Alk¹ where Alk¹ is astraight or branched C₁₋₆ alkylene, C₂₋₆alkenylene, or C₂₋₆alkynylenechain optionally interrupted by one, two, or three —O—, or —S— atoms or—S(O)_(z)—, (where z is an integer 1 or 2) or —N(R^(b))— groups; or is agroup Ar″ (where Ar″ is as defined for Ar), —SO₃H, —SO₂R″, —SO₂NH₂,—SO₂NHR″ —SO₂N[R″]₂, —CONH₂, —CONHR″ —CON[R″]2, —NHSO₂H, —N(R″)SO₂H,—NHSO₂R″, —NR″SO₂R″, —N[SO₂R″1₂, —NHSO₂NH₂, —NR″SO₂ NH₂, —NHSO₂ NHR″,—NR″SO₂NHR″, —NHSO₂NHR″]₂, —N(R″)SO₂N[R″]₂, —NHC(O)R″, —NR″C(O)R″,—N[C(O)R″]₂, —NHC(O)H, —NR″C(O)H, —NHC(O)OR″, —NR″C(O)OR″, —NHC(O)OH,—NR″C(O)OH, —NHCONH₂, —NHCONHR″, —NHCON[R″]₂, —NR″CON[R″]₂, —C(S)R″,—C(S)NH₂, —C(S)NHR″, —C(S)N[R″₂, —NHC(S)R″, —NR″C(S)R″, -N[[C(S)R″]₂,—NHC(S)H, —NR″C(S)H, —NHC(S)NH₂, —NHC(S)NHR″, —NHC(S)N[R″]₂,—NR″C(S)N[R″]₂, ″Ar″ or —XAr″ group; and m is zero or an integer 1, 2 or3.

[0048] When in the group -Alk¹(R¹⁵)_(m) m is an integer 1, 2 or 3, it isto be understood that the substituent or substituents R¹⁵ may be presenton any suitable carbon atom in -Alk¹. Where more than one R¹⁵substituent is present these may be the same or different and may bepresent on the same or different carbon atom in Alk¹. Clearly, when m iszero and no substituent R¹⁵ is present or when Alk¹ forms part of agroup such as —SO₂Alk¹ the alkylene, alkenylene or alkynylene chainrepresented by Alk¹ becomes an alkyl, alkenyl or alkynyl group.

[0049] When R¹⁵ is a substituted amino group it may be a group—NH[Alk¹(R^(15a))m] [where Alk¹ and m are as defined above and R^(15a)is as defined above for R¹⁵ but is not a substituted amino, asubstituted hydroxyl or a substituted thiol group] or a group —N[Alk¹(R^(15a))m]2 wherein each -Alk¹ (R^(15a))_(m) group is the same ordifferent.

[0050] When R¹⁵ is a halogen atom it may be for example a fluorine,chlorine, bromine, or iodine atom.

[0051] When R¹⁵ is a cycloalkoxy group it may be for example aC₅₋₇cycloalkoxy group such as a cyclopentyloxy or cyclohexyloxy group.When R¹⁵ is a substituted hydroxyl or substituted thiol group it may bea group —OAlk¹(R^(15a))_(m) or —SAlk¹(R^(15a))_(m) respectively, whereAlk¹, R^(5a) and m are as just defined.

[0052] Esterified carboxyl groups represented by the group R¹⁵ includegroups of formula —CO₂Alk² wherein Alk² is a straight or branched,optionally substituted C₁₋₈alkyl group such as a methyl, ethyl,n-propyl, 1-propyl, n-butyl, 1-butyl, s-butyl or t-butyl group; aC₆₋₁₂arylC₁₋₈alkyl group such as an optionally substituted benzyl,phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; aC₆₋₁₂aryl group such as an optionally substituted phenyl, 1-naphthyl or2-naphthyl group; a C₆₋₁₂aryloxyC₁₋₈alkyl group such as an optionallysubstituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or2-naphthyloxymethyl group; an optionally substitutedC1-8alkanoyloxyC₆₋₈alkyl group, such as a pivaloyloxymethyl,propionyloxyethyl or propionyloxypropyl group; or aC₆₋₁₂aroyloxyC₁₋₈alkyl group such as an optionally substitutedbenzoyloxyethyl or benzoyloxy-propyl group. Optional substituentspresent on the Alk² group include R¹⁴ substituents described above.

[0053] When the group R¹⁵ in compounds of formulae (1) and (2) is anoptionally substituted C₃₋₉cycloaliphatic group, it may be aC₃₋₉cycloalkyl or C₃₋₉cycloalkenyl group such as a C5-7cycloalkyl orC5-7Cycloalkenyl group, containing 1, 2, 3 or more heteroatoms selectedfrom oxygen, sulphur or nitrogen atoms. Particular examples of such R¹⁵groups include pyrrolyl, e.g. 2H-pyrrolyl, pyrrolinyl, e.g. 2— or3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, imidazolinyl, e.g.2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl,pyrazolidinyl, pyranyl, e.g. 2— or 4-pyranyl, piperidinyl, 1,4-dioxanyl,morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl,1,3,5-trithianyl, 3H-pyrrolyl, 2H-imidazolyl, dithiolyl, e.g. 1,2— or1,3-dithiolyl, oxathiolyl, e.g. 3H-1-2 or 1,3-oxathiolyl,5H-1,2,5-oxathiozolyl, 1,3-dioxinyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-,6H-1,2-, 1,4-2H-1,2— or 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl,e.g. -o- or p- isoxazinyl, oxathiazinyl, e.g. 1,2,5-,1,2,6-oxathiazinyl, 1,3,5,2-oxadiazinyl, or 1,2,4-diazepinyl groups.Optional substituents which may be present on such groups include thosesubstituents discussed above in relation to the group Ar′ where Ar′ is aheterocycloaliphatic group.

[0054] It will be appreciated that the group Ar, Ar′ or R′ may beattached to the remainder of the molecule of formula (1) through eithera ring carbon atom or heteroatom.

[0055] Particular examples of the group Alk¹ when present includemethylene, ethylene, n-propylene, 1-propylene, n-butylene, 1-butylene,s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene,3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylenechain, optionally interrupted by one, two, or three —O— or —S— atoms or—S(O)—, —S(O)2— or —N(R^(b))— groups.

[0056] Particularly useful atoms or groups represented by R¹⁴ includefluorine, chlorine, bromine or iodine atoms, or C₁₋₆alkyl, e.g. methylor ethyl, C₁₋₆alkylamino, e.g. methylamino or ethylamino, C₁₋₆hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, C₁₋₆alkylthiol e.g.methylthiol or ethylthiol, C₁₋₆-alkoxy, e.g. methoxy or ethoxy,C₅₋₇cycloalkyl e.g. cyclopentyl, C₅₋₇ cycloalkoxy, e.g. cyclopentyloxy,haloC₁₋₆alkyl, e.g. trifluoromethyl, C₁₋₆ alkylamino, e.g. methylaminoor ethylamino, amino (—NH₂), aminoC₁₋₆alkyl, e.g. aminomethyl oraminoethyl, C₁₋₆-dialkylamino, e.g. dimethylamino or diethylamino,nitro, cyano, hydroxyl (—OH), formyl [HC(O)—], carboxyl (—CO₂H),—CO₂Alk² [where Alk² is as defined above], C₁₋₆ alkanoyl e.g. acetyl,thiol (—SH), thioC₁₋₆alkyl, e.g. thiomethyl or thioethyl, sulphonyl(—SO₃H), C₁₋₆alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl(—SO₂NH₂), C₁₋₆alkylaminosulphonyl, e.g. methylaminosulphonyl orethyl-aminosulphonyl, C₁₋₆dialkylaminosulphonyl, e.g.dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl,carboxamido (—CONH₂), C₁₋₆alkylaminocarbonyl, e.g. methylaminocarbonylor ethylaminocarbonyl, C₁₋₆dialkylaminocarbonyl, e.g.dimethylaminocarbonyl or diethylamino-carbonyl, phenylaminocarbonyl,sulphonylamino (—NHSO₂H), C₁₋₆alkyl-sulphonylamino, e.g.methylsulphonylamino or ethylsulphonylamino, C₁₋₆ dialkylsulphonylamino,e.g. dimethylsulphonylamino or diethylsulphonyl-amino,aminosulphonylamino (—NHSO₂NH₂), C₁₋₆alkylaminosulphonyl-amino, e.g.methylaminosulphonylamino or ethylaminosulphonylamino,C₁₋₆dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino ordiethylaminosulphonylamino, phenylaminosulphonylamino,C₁₋₆alkanoyl-amino, e.g. acetylamino, C₁₋₆alkanoylaminoCi 6alkyl, e.g.acetylamino-methyl or C₁₋₆ alkoxycarbonylamino, e.g.methoxycarbonylamino, ethoxy-carbonylamino or t-butoxycarbonylamino,thiocarboxamido (—CSNH₂), C₁₋₆ alkylaminothiocarbonyl, e.g.methylaminothiocarbonyl or ethylamino-thiocarbonyl,C₁₋₆dialkylaminothiocarbonyl, e.g. dimethylaminothio-carbonyl ordiethylaminothiocarbonyl, aminocarbonylamino,C₁₋₆alky-aminocarbonylamino, e.g. methylaminocarbonylamino orethylamino-carbonylamino, C₁₋₆dialkylaminocarbonylamino, e.g.dimethylamino-carbonylamino or diethylaminocarbonylamino,aminothiocarbonylamino, C₁₋₆alkylaminothiocarbonylamino, e.g.methylaminothiocarbonylamino or ethylaminothiocarbonylamino,C₁₋₆dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino,or diethylaminothiocarbonylamino, aminocarbonylC₁₋₆alkylamino, e.g.aminocarbonylmethylamino or amino-carbonylethylamino,aminothiocarbonylC₁₋₆alkylamino e.g. aminothio-carbonylmethylamino oraminothiocarbonylethylamino, formylaminoC₁-6 alkylsulphonylamino, e.g.formylaminomethylsulphonylamino or formyl-aminoethylsulphonylamino,thioformylaminoC₁₋₆alkylsulphonylamino, e.g.thioformylaminomethylsulphonylamino or thioformylethylsulphonylamino,C₁₋₆acylaminosulphonylamino, e.g. acetylaminosulphonylamino,C₁₋₆thio-acylaminosulphonylamino, e.g. thioacetylaminosulphonylaminogroups, —Ar″, e.g. phenyl, —XAr″ e.g. phenoxy, or -Alk′ Ar″ e.g. benzylor phenethyl groups.

[0057] Where desired, two R¹⁴ substituents may be linked together toform a cyclic group such as a cyclic ether, e.g. a C₂₋₆alkylenedioxygroup such as ethylenedioxy.

[0058] It will be appreciated that where two or more R¹⁴ substituentsare present, these need not necessarily be the same atoms and/or groups.The R¹⁴ substituents may be present at any ring carbon atom away fromthat attached to the rest of the molecule of formula (1). Thus, forexample, in phenyl groups represented by Ar any substituent may bepresent at the 2-, 3-, 4-, 5- or 6-positions relative to the ring carbonatom attached to the remainder of the molecule.

[0059] Particular examples of the chain Z¹ in compounds of formula (1)include —NHCO—, —CONH—, —NHCS—, —CSNH—, —NHSO₂—, —SO₂NH— and —C═C—.

[0060] In the compounds of formula (1), when an ester group is present,for example a group —CO₂R⁸ or —CO₂Alk² this may advantageously be ametabolically labile ester.

[0061] The presence of certain substituents in the compounds of formula(1) may enable salts of the compounds to be formed. Suitable saltsinclude pharmaceutically acceptable salts, for example acid additionsalts derived from inorganic or organic acids, and salts derived frominorganic and organic bases.

[0062] Acid addition salts include hydrochlorides, hydrobromides,hydroiodides, alkylsulphonates, e.g. methanesulphonates,ethanesulphonates, or isethionates, arylsulphonates, e.g.p-toluenesulphonates, besylates or napsylates, phosphates, sulphates,hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates,maleates, fumarates, malonates, succinates, lactates, oxalates,tartrates and benzoates.

[0063] Salts derived from inorganic or organic bases include alkalimetal salts such as sodium or potassium salts, alkaline earth metalsalts such as magnesium or calcium salts, and organic amine salts suchas morpholine, piperidine, dimethylamine or diethylamine salts.

[0064] Prodrugs of compounds of formula (1) include those compounds, forexample esters, alcohols or aminos, which are convertible in vivo bymetabolic means, e.g. by hydrolysis, reduction, oxidation ortrans-esterification, to compounds of formula (1).

[0065] Particularly useful salts of compounds according to the inventioninclude pharmaceutically acceptable salts, especially acid additionpharmaceutically acceptable salts. In the compounds of formula (1) thegroup ═W— is preferably a ═C(Y)— group. In compounds of this type Y ispreferably a —XR^(a) group where X is —O— and R^(a) is an optionallysubstituted ethyl group or, especially, an optionally substituted methylgroup. Especially useful substituents which may be present on R^(a)groups include one, two or three fluorine or chlorine atoms.

[0066] The group L in compounds of formula (1) is preferably a—CH═C(R¹)(R²) group. In compounds of this type R¹ and R² are preferablylinked together with the C atom to which they are attached to form anoptionally substituted cycloalkyl or cycloalkenyl group, especially asubstituted cyclopentyl or cyclohexyl or, especially, a cyclopentyl orcyclohexyl group.

[0067] In the compounds of formula (1) where Z is the group (A), onepreferred group of compounds are those where the group R³ is a hydrogenatom; the group R⁶ is a methyl group, or especially a hydrogen atom; thegroup R⁷ is a methyl group, or especially a hydrogen atom; and R⁴ and R⁵are as defined for formula (1). In compounds of this type R⁶ and R⁷ inone preference, is each a methyl group; in another preference, one of R⁶or R⁷ is a methyl group and the other is a hydrogen atom, in general,however, R⁶ and R⁷ is each especially a hydrogen atom.

[0068] The groups R⁴ and R⁵ when present in compounds of formula (1) areeach, independently, preferably a —CH₂Ar group, or, especially, an —Argroup. Particularly useful R⁴ or R⁵ groups of this type include thosegroups in which Ar is a monocyclic aryl group optionally containing oneor more heteroatoms selected from oxygen, sulphur, or, in particular,nitrogen atoms, and optionally substituted by one, two, three or moreR¹⁴ substituents. In these compounds, when the group represented by Aris a heteroaryl group it is preferably a nitrogen-containing monocyclicheteroaryl group, especially a six-membered nitrogen-containingheteroaryl group. Thus, in one preferred example, the groups R⁴ and R⁵may each be a six-membered nitrogen-containing heteroaryl group. Inanother preferred example R⁴ may be a monocyclic aryl group or amonocyclic or bicyclic heteroaryl group containing one or more oxygen,sulphur or nitrogen atom and R⁵ may be a six-memberednitrogen-containing heteroaryl group. In these examples, thesix-membered nitrogen-containing heteroaryl group may be an optionallysubstituted pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or imidazolylgroup. Particular examples include optionally substituted 2-pyridyl,3-pyridyl, 5-imidazolyl, or, especially, 4-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 2-pyrazinyl or 3-pyrazinyl. The monocyclic aryl group maybe a phenyl group or a substituted phenyl group, and the monocyclic orbicyclic heteroaryl group containing one or more oxygen, sulphur ornitrogen atom may be an optionally substituted 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-thiazolyl, 2-benzo(b)thiophenyl, 2-benzo(b)furylor 4-isoquinolinyl group.

[0069] One particularly useful group of compounds of formula (1) when Zis a group (A) or (B) is that wherein R⁴ and R⁵ is each a pyridyl or,especially, a monosubstituted pyridyl, or preferably a disubstitutedpyridyl group, or R⁴ is a phenyl, thienyl or furyl, or substitutedphenyl, thienyl or furyl group and R⁵ is a pyridyl or, especially amonosubstituted pyridyl, or preferably a disubstituted pyridyl group.

[0070] In this particular group of compounds and also in general incompounds of formula (1) when R⁴ and/or R⁵ is a substituted phenyl groupit may be for example a mono-, di- or trisubstituted phenyl group inwhich the substituent is an atom or group R¹⁴ as defined above. When theR⁴ and/or R⁵ group is a monosubstituted phenyl group the substituent maybe in the 2-, or preferably 3-, or especially 4-position relative to thering carbon atom attached to the remainder of the molecule. When the R⁴and/or R⁵ group is a disubstituted phenyl group, the substituents may bein the 2,6 position relative to the ring carbon atom attached to theremainder of the molecule.

[0071] When in compounds of formula (1) R⁴ and/or R⁵ is a substitutedpyridyl group it may be for example a mono-or disubstituted pyridylgroup, such as a mono- or disubstituted 2-pyridyl, 3-pyridyl orespecially 4-pyridyl group substituted by one or two atoms or groups R¹⁴as defined above, in particular one or two halogen atoms such asfluorine or chlorine atoms, or methyl, methoxy, hydroxyl or nitrogroups. Particularly useful pyridyl groups of these types are3-monosubstituted-4-pyridyl or 3,5-disubstituted-4-pyridyl, or 2— or4-monosubstituted-3-pyridyl or 2,4-disubstituted-3-pyridyl groups.

[0072] Other particularly useful groups of compounds of formula (1)where Z is the group (B), include those where R⁴ is a —CH₃ group or ahydrogen atom; R⁵ is a hydrogen atom, a —CN or a —CH₃ group; R⁶ is asjust described for R⁴ and R⁵ in the compounds of formula (1) where Z isthe group (A).

[0073] Another particularly useful group of compounds of formula (1)when Z is a group (C) is that wherein Ar is a phenyl, naphthyl,pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl,pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl,5,6,7,8-tetrahydroquinolinyl or 5,6,7,8-tetrahydro-isoquinolinyl group.In compounds of this type when Ar is a quinolinyl group it may be forexample a mono- or disubstituted quinolinyl group such as a2-monosubstituted-4-quinolinyl group; when it is a pyridyl group, it maybe an optionally substituted 3— or 4— pyridyl, e.g. a2,3,5,6-tetrasubstituted-4-pyridyl or 2,4,6-trisubstituted-3-pyridylgroup; when it is a pyrimidinyl group, it may be for example a5-pyrimidinyl group or a 2-substituted 5-pyrimidinyl group; and when itis an isoquinolinyl group, it may be a 4-isoquinolinyl group.

[0074] Other especially useful groups of compounds of formula (1)include those where Z is a group (D) in which (1) —Z¹ is a —C(O)NR¹²—group, where R¹² is a hydrogen atom. In compounds of this type, t ispreferably zero and Ar is a 2-nitrophenyl or 4-(3,5-dichloro)pyridylgroup, or (2) those where —Z¹— is a —NR¹²C(O)— group, where R¹² is ahydrogen atom, t is zero and Ar is a 4-pyridyl or4-(3,5-dichloro)pyridyl, benzyl or 2-methylbenzoate group, or t is aninteger of value 1 and Ar is a 2— or 3-nitrophenyl, phenyl or2-methylphenyl group.

[0075] A particularly useful group of compounds of formula (1) has theformula (2):

[0076] where (1) —L is a —CH═C(R¹)(R²) or —CH₂CH(R¹)(R²) group where R¹and R² are linked together with the carbon atom to which they areattached to form a cycloalkyl group: or (2) L is a group —OAlkAr′ whereAlk is a C₁₋₆alkylene chain and Ar′ is a monocyclic aryl or heteroarylgroup. Particular examples of such L groups include benzyloxy,thienyloxy or phenyl-pentyloxy groups; or (3) L is a group OR′ where R′is an optionally substituted polycyloalkyl or polycycloalkenyl group oris as described above for Ar′. Preferred examples of such R′ groupsinclude optionally substituted bicycylo[2.2.1]heptyl orbicyclo[2.2.1]heptenyl group. In particular R′ is abicyclo[2.2.1]hept-2-yl group; and Z is as defined for formula (1); andthe salts, solvates, hydrates, prodrugs and N-oxides thereof.

[0077] In compounds of formula (2) where R³, R⁶ or R⁷ is present it iseach preferably a hydrogen atom.

[0078] A particularly useful group of compounds according to theinvention has the formula (2) wherein L is a OR′ group and Z is thegroup (A). In this particular group of compounds R³, R⁶ and R⁷ is each ahydrogen atom and R⁴ and R⁵ are as defined for compounds of formula (1)and the salts, solvates, hydrates and N-oxides thereof. Compounds ofthis type in which R′ is a bicyclo [2.2.1] heptyl, particularly abicyclo [2.2.1] hept-2-yl group are particularly useful. In this groupof compounds, R⁴ is preferably a monocyclic aryl group, particularly aphenyl or substituted phenyl group or R⁴ is a six-memberednitrogen-containing monocyclic heteroaryl group, particularly a pyridylor substituted pyridyl group and R⁵ is a six-memberednitrogen-containing monocyclic heteroaryl group, especially a pyridyl orsubstituted pyridyl group, in particular a 4-pyridyl or substituted4-pyridyl group.

[0079] Other particularly useful groups of compounds of formulae (1) or(2) where L is a group —C(R)═C(R¹)(R²) or —(X^(a))_(n)Alk′Ar′ and Z isthe group (B), include those where R⁴ is a —CH₃ group or a hydrogenatom; R⁵ is a hydrogen atom, a —CN or a —CH₃ group; R⁶ is as justdescribed for R⁴ and R⁵ in the compounds of formulae (1) or (2) where Zis the group (A).

[0080] Particular compounds according to the invention are:

[0081] (2R)-4-{2-[3-((2RS)-exo-Bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]-2-phenylethyl}pyridine;

[0082] (±)-4-[2-(3-Benzyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine;

[0083](±)-4-{2-[4-Methoxy-3-(3-thienyloxy)phenyl]-2-phenylethyl}pyridine;

[0084](±)-4-[2-(3-Cyclopentylidenyl-4-methoxyphenyl)-2-phenylethyl]pyridine;

[0085](±)-4-[2-(3-Cyclohexylidenyl-4-methoxyphenyl)-2-phenylethyl]pyridine;

[0086] (E,Z)-3-(3-Cyclopentylidenyl-4-methoxyphenyl)-2-(2,6-dichlorophenyl)propenenitrile;

[0087] (E,Z)-3-(3-Cyclopentylidenyl-4-methoxyphenyl)-2-(2,6-difluorophenyl)propenenitrile;

[0088] (E,Z)-4-[2-(3-Cyclopentylidenyl-4-methoxyphenyl)ethenyl]-3,5-dichloro-pyridine;

[0089] 3-(3-Cyclopentylidenyl-4-methoxyphenyl)pyridine;

[0090] 5-(3-Cyclopentylidenyl-4-methoxyphenyl)pyrimidine;

[0091] 4-(3-Cyclopentylidenyl-4-methoxyphenyl)nitrobenzene;

[0092] 3-(3-Cyclopentylmethyl-4-methoxyphenyl)pyridine;

[0093]N-(3-Cyclopentylidenyl-4-methoxyphenyl)-3,5-dichloro-4-pyridenecarbox-amide;

[0094] 4-[2-(3-Cyclopentylidenyl-4-methoxyphenyl)ethyl]pyridine;

[0095]N-{4-[2-(3-Cyclopentylidenyl-4-methoxyphenyl)ethyl]-3-pyridyl}phenyl-sulphonamide;

[0096] 3-Cyclopentylidenyl-4-methoxy-N-(2-nitrobenzoyl)aniline;

[0097] N-(3-Cyclopentylidenyl-4-methoxyphenyl)-4-pyridinecarboxam ide;

[0098] N-Phenyl-3-cyclopentylidenyl-4-methoxybenzam ide;

[0099] N-(2—Nitrophenyl)-3-cyclopentylidenyl-4-methoxybenzamide;

[0100]N-(3,5-Dichloropyrid-4-yl)-3-cyclopentylidenyl-4-methoxybenzamide;

[0101] and the salts, solvates, hydrates, prodrugs and N-oxides thereof.

[0102] Compounds according to the invention are selective and potentinhibitors of PDE IV. The ability of the compounds to act in this waymay be simply determined by the tests described in the Exampleshereinafter.

[0103] Particular uses to which the compounds of the invention may beput include the prophylaxis and treatment of asthma, especially inflamedlung associated with asthma, cystic fibrosis, or in the treatment ofinflammatory airway disease, chronic bronchitis, eosinophilic granuloma,psoriasis and other benign and malignant proliferative skin diseases,endotoxic shock, septic shock, ulcerative colitis, Crohn's disease,reperfusion injury of the myocardium and brain, inflammatory arthritis,chronic glomerulonephritis, atopic dermatitis, urticaria, adultrespiratory distress syndrome, diabetes insipidus, allergic rhinitis,allergic conjunctivitis, vernal conjunctivitis, arterial restenosis andartherosclerosis.

[0104] Compounds of the invention may also suppress neurogenicinflammation through elevation of cAMP in sensory neurones. They are,therefore, analgesic, anti-tussive and anti-hyperalgesic in inflammatorydiseases associated with irritation and pain.

[0105] Compounds according to the invention may also elevate cAMP inlymphocytes and thereby suppress unwanted lymphocyte activation inimmune-based diseases such as rheumatoid arthritis, ankylosingspondylitis, transplant rejection and graft versus host disease.

[0106] Compounds according to the invention may also reduce gastric acidsecretion and therefore can be used to treat conditions associated withhypersecretion.

[0107] Compounds of the invention may suppress cytokine synthesis byinflammatory cells in response to immune or infectious stimulation. Theyare, therefore, useful in the treatment of bacterial, fungal or viralinduced sepsis and septic shock in which cytokines such as tumournecrosis factor (TNF) are key mediators. Also compounds of the inventionmay suppress inflammation and pyrexia due to cytokines and are,therefore, useful in the treatment of inflammation and cytokine-mediatedchronic tissue degeneration which occurs in diseases such as rheumatoidor osteo-arthritis.

[0108] Over-production of cytokines such as TNF in bacterial, fungal orviral infections or in diseases such as cancer, leads to cachexia andmuscle wasting. Compounds of the invention may ameliorate these symptomswith a consequent enhancement of quality of life.

[0109] Compounds of the invention may also elevate cAMP in certain areasof the brain and thereby counteract depression and memory impairment.

[0110] Compounds of the invention may suppress cell proliferation incertain tumour cells and can be used, therefore, to prevent tumourgrowth and invasion of normal tissues.

[0111] For the prophylaxis or treatment of disease the compoundsaccording to the invention may be administered as pharmaceuticalcompositions, and according to a further aspect of the invention weprovide a pharmaceutical composition which comprises a compound offormula (1) together with one or more pharmaceutically acceptablecarriers, excipients or diluents.

[0112] Pharmaceutical compositions according to the invention may take aform suitable for oral, buccal, parenteral, nasal, topical or rectaladministration, or a form suitable for administration by inhalation orinsufflation.

[0113] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles and preservatives. Thepreparations may also contain buffer salts, flavouring, colouring andsweetening agents as appropriate.

[0114] Preparations for oral administration may be suitably formulatedto give controlled release of the active compound.

[0115] For buccal administration the compositions may take the form oftablets or lozenges formulated in conventional manner.

[0116] The compounds of formulae (1) and (2) may be formulated forparenteral administration by injection e.g. by bolus injection orinfusion. Formulations for injection may be presented in unit dosageform, e.g. in glass ampoule or multi dose containers, e.g. glass vials.The compositions for injection may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising, preserving and/ordispersing agents. Alternatively, the active ingredient may be in powderform for constitution with a suitable vehicle, e.g. sterile pyrogen-freewater, before use.

[0117] In addition to the formulations described above, the compounds offormulae (1) and (2) may also be formulated as a depot preparation. Suchlong acting formulations may be administered by implantation or byintramuscular injection.

[0118] For nasal administration or administration by inhalation, thecompounds for use according to the present invention are convenientlydelivered in the form of an aerosol spray presentation for pressurisedpacks or a nebuliser, with the use of suitable propellant, e.g.dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

[0119] The compositions may, if desired, be presented in a pack ordispenser device which may contain one or more unit dosage formscontaining the active ingredient. The pack or dispensing device may beaccompanied by instructions for administration.

[0120] The quantity of a compound of the invention required for theprophylaxis or treatment of a particular inflammatory condition willvary depending on the compound chosen, and the condition of the patientto be treated. In general, however, daily dosages may range from around100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weightfor oral or buccal administration, from around 10 ng/kg to 50 mg/kg bodyweight for parenteral administration and around 0.05 mg to around 1000mg e.g. around 0.5 mg to around 1000 mg for nasal administration oradministration by inhalation or insufflation.

[0121] The compounds according to the invention may be prepared by thefollowing processes. The symbols W, L, Z, X, R¹, R², R³, R⁴, R⁵, R⁶, andR⁷ when used in the formulae below are to be understood to representthose groups described above in relation to formula (1) unless otherwiseindicated. In the reactions described below it may be necessary toprotect reactive functional groups, for example hydroxy, amino, thio,carboxy or aldehyde groups, where these are desired in the finalproduct, to avoid their unwanted participation in the reactions.Conventional protecting groups may be used in accordance with standardpractice (see, for example, Green, T. W. in “Protective Groups inOrganic Synthesis” John Wiley and Sons, 1981].

[0122] Thus, according to a further aspect of the invention, compoundsof general formula (1) where L is X^(a)Alk′Ar′, Alk′X^(a)Ar′ or X^(a)R′may be prepared by coupling an intermediate of formula (3)

[0123] a) where L² is a group —X^(a)H with a reagent L³Alk′Ar′, or L³R′where L³ is a leaving group; or

[0124] b) where L² is a group -Alk′L³ with a reagent Ar′X^(a)H.

[0125] Leaving groups represented by L³ include halogen atoms such asiodine, chlorine or bromine atoms, sulphonyloxy groups such asarylsulpyhonyl-oxy groups, e.g. ptoluenesulphonyloxy or hydroxyl groups.

[0126] The coupling reaction may be carried out in the presence of abase, e.g. an inorganic base such as a carbonate, e.g. caesium orpotassium carbonate, an alkoxide, e.g. potassium t-butoxide, or ahydride, e.g. sodium hydride, in a dipolar aprotic solvent such as anamide, e.g. a substituted amide, such as dimethylformamide or an ether,e.g. diethylether or a cyclic ether such as tetrahydrofuran orhalogenated solvents, such as dichloromethane. The temperature of thereaction mixture may vary from ambient temperature or above, e.g. around40° C. to the reflux temperature. Where necessary, an activator may beused, such as diethyl-, diisopropyl-, or dimethylazodicarboxylate, inthe presence of a phosphine, such as triphenylphosphine and a base, suchas an amine, e.g. triethylamine.

[0127] Intermediates of formula (3) where L² is a group -Alk′L³ whereinL³ is a halogen atom may be prepared by reaction of an intermediate offormula (3) wherein Alk′L³ is a -Alk′OH group with a halogenating agent,such as an inorganic acid halide e.g. thienylchloride, or an anhydridesuch as an arylsulphonic anhydride, e.g. p.toluenesulphonic anhydride,using conventional procedures.

[0128] Intermediates of formula (3) where L² is a group —X^(a)H may beprepared by deprotection of a protected compound of formula (4)

[0129] where P is a hydroxy, thio, or amino protecting group. Examplesof hydroxy protecting groups include, for example ether groups, such asa cyclopentyloxy group. The deprotection reaction may take place in anaqueous solvent, such as an aqueous ether, e.g. dioxane-water, in thepresence of an acid, e.g. sulphuric acid at an elevated temperature.e.g. around 90° C. Another example of protecting group P includet-butyidimethylsilyloxy group which can be cleaved by treatment withtetrabutylammonium fluoride to regenerate the free hydroxy group.

[0130] Intermediates of formula (3) where Z is a group (A) in which R³is a hydroxyl group and R⁷ is a hydrogen atom may be prepared byreacting a ketone of formula (5)

[0131] with an organometallic reagent R⁵R⁶ CHM, where M is a metal atom.

[0132] Metal atoms represented by Z include, for example, a lithiumatom.

[0133] The reaction may be performed in a solvent such as an ether, e.g.a cyclic ether such as tetrahydrofuran, at a low temperature e.g. around−70° C. to ambient temperature. This reaction is particularly suitablefor the preparation of compounds of formula (3) wherein R⁵ is anelectron deficient group such as a 2— or 4-pyridyl group.

[0134] Reagents R⁵R⁶CHM are either known compounds or may be prepared,preferably in situ during the above process, by reaction of a compoundAlkCH₂M [where Alk is an alkyl group such as n-propyl] with a compoundR⁵R⁶CH₂ where necessary in the presence of a base such as an amine e.g.diisopropylamine using the above-mentioned conditions.

[0135] Intermediates of formula (5) where L² is a group —X^(a)H in which—X^(a)— is —NH-and R⁴ is a hydrogen atom may be prepared from the knowncompound of formula (6)

[0136] by reduction with a reducing agent, such as a lithium aluminiumhydride, to give the alcohol derivative. This in turn may be oxidised,for example with manganese dioxide to afford an aldehyde of formula (5).

[0137] Intermediates of formula (3) where Z is a group (A) in which R³is a hydroxyl group may be prepared by reacting a ketone of formula (5)with a reagent R⁵CHR⁶R⁷ using a base, such as an organometallic base,for example an organolithium reagent e.g. n-butyllithium, in a solvent,such as an ether, e.g. tetrahydrofuran, at around −70° C. to roomtemperature. Ketones of formula (5) may be prepared by oxidation of analcohol of formula (7)

[0138] using an oxidising agent, such as manganese (IV) oxide, in asolvent, such as dichloromethane, at room temperature.

[0139] Alternatively, ketones of formula (5) may be prepared by reactionof a halide of formula (8)

[0140] [where Hal is a halogen atom such as a bromine or chlorine atom]by halogen-metal exchange with a base such as n-butyllithium followed byreaction with a nitrile R⁴CN, an acid chloride R⁴COCl or an ester R⁴CO₂A(where A is an alkyl group, e.g. a methyl group), in a solvent such astetrahydrofuran at a low temperature, e.g. around −70° C., andsubsequent treatment with an acid such as hydrochloric acid at e.g. −20°C. to ambient temperature.

[0141] Alcohols of Formula (7) may be Prepared

[0142] (1) by reacting a halide of formula (8) e.g. a bromide, with analdehyde R⁴CHO, in the presence of a base, such as n-butyllithium, in asolvent, e.g. tetrahydrofuran, at a temperature from around −70° C. toroom temperature; or

[0143] (2) by reacting an aldehyde of formula (9) where W^(a) is a —CHOgroup (as described hereinbelow) with an organometallic compound, suchas an organolithium R⁴Li, or a Grignard R⁴MgBr, in a solvent, such astetrahydrofuran, at a low temperature, e.g. around −55° C. to 0° C.

[0144] Intermediates of formula (3) where Z is a group (B) may beprepared by condensing an intermediate of formula (9)

[0145] where

[0146] (a) W^(a) is a —C(O)R⁴ group wherein R⁴ is as defined for formula(1) but is not a —CN or —CH₂CN group, with a compound R⁵CH₂R⁶; or where

[0147] (b) W^(a) is a —CH₂R⁴ group with an aldehyde or ketone R⁵COR⁶where R⁵ is as just defined for R⁴; or where

[0148] (c) W^(a) is a —C(O)R⁴ group with a silane derivative(Alk^(a))₃SiCH(R⁵)(R⁶), where Alk^(a) is an alkyl group; in eachinstance in the presence of a base or an acid in a suitable solvent.

[0149] Bases for use in these reactions include inorganic bases, forexample alkali and alkaline earth metal bases, e.g. hydroxides, such assodium or potassium hydroxide; alkoxides, for example sodium ethoxide;organic bases, for example amines such as piperidine; and organolithiumbases, such as alkyllithium, e.g. n-butyllithium bases. Suitablesolvents include alcohols such as ethanol, or ethers such astetrahydrofuran. Acids for use in the reactions include organic acids,e.g. carboxylic acids such as acetic acid.

[0150] The reactions may be performed at any suitable temperature, forexample from around −78° C. to ambient temperature or to the refluxtemperature depending on the nature of the starting materials.

[0151] In general, the base, acid, solvent and reaction conditions maybe selected depending on the nature of the starting materials, from arange of known alternatives for reactions of this type.

[0152] In silane derivatives of formula (Alk^(a))₃SiCH(R⁵)(R⁶), Alk^(a)may be for example a C₁₋₆alkyl group such as a methyl group. Derivativesof this type may be prepared for example by reacting a compoundR⁵—CH₂—R⁶ with a silane derivative, such as a chlorotrialkylsilane, e.g.chlorotrimethyl-silane in the presence of a base, e.g. lithiumdiisopropylamide, in a solvent, e.g. tetrahydrofuran, at a lowtemperature, e.g. around −10° C.

[0153] The starting materials R⁵COR⁶ and R⁵ CH₂R⁶ are either knowncompounds or may be prepared from known starting materials by methodsanalogous to those used for the preparation of the known compounds.

[0154] Intermediates of formula (9) where —W^(a) is a —C(O)R⁴ groupwhere R⁴ is an alkyl or aryl group (CH₂)_(t)Ar group, may be prepared byreacting an aldehyde of formula (9) where —W^(a) is a —CHO group with anorganometallic reagent in a solvent, e.g. tetrahydrofuran, at lowtemperature, e.g. around 10° C., followed by oxidation with an oxidisingagent, such as manganese dioxide, in a solvent, e.g. dichloromethane.

[0155] Intermediates of formula (9) where —W^(a) is —CHO may be preparedby reacting a compound of formula (8) described above with anorgano-metallic reagent, such as n-butyllithium, in a solvent, such asan amide, e.g. dimethylformamide, at a low temperature, e.g. below −60°C.

[0156] Intermediates of formula (8) may be prepared by deprotecting acompound of formula (10)

[0157] using reagents and conditions described herein for the obtentionof an intermediate of formula (3) from an intermediate of formula (4)where L² is a group X^(a)H.

[0158] Intermediates of formula (10) may be prepared by protecting acompound of formula (11)

[0159] Examples of protecting groups include hydroxy, thio or aminoprotecting groups using conventional procedures [see Green, T. W. ibid].Thus for example, where X^(a) is an oxygen atom, the hydroxyl group maybe protected as an ether group, using a reagent Alk^(b)L³, where Alk^(b)is an alkyl group and L³ is a leaving group. Alkyl groups represented byAlk^(b) include cycloalkyl groups, such as cyclopentyl group, andleaving groups L³ include halogen atoms such as iodine, chlorine orbromine atoms or sulphonyloxy groups such as arylsulphonyloxy groups,e.g. p.toluene-sulphonyloxy groups.

[0160] The reaction may be carried out in the presence of a base, e.g.an inorganic base such as a carbonate, e.g. caesium or potassiumcarbonate, an alkoxide, e.g. potassium-t-butoxide, or a hydride, e.g.sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. asubstituted amide such as dimethylformamide or an ether, e.g. a cyclicether such as tetrahydrofuran, at ambient temperature or above. e.g.around 40° C. to 50° C.

[0161] Halides of formula (11) where X^(a) is —O— may be prepared byoxydation of an aldehyde of formula (17) (where R is a hydrogen atom) asdescribed below using an oxidising agent such as 3-chloroperoxybenzoicacid in a halogenated hydrocarbon such as chloroform at a temperaturefrom around 0° C. to room temperature. Halides of formula (11) whereX^(a) is —S— or —N(R^(b))— are either known compounds or may be preparedfrom known starting materials by methods analogous to those used for thepreparation of the known compounds.

[0162] Compounds of formula (1) where Z is a group (A) in which R³ is ahydroxyl group and R⁷ is as described for compounds of formula (1) maybe prepared by reacting a compound or formula (11) with a reagentR⁵R⁶CHM or R⁵CHR⁶R⁷ using the conditions described hereinabove for theobtention of an intermediate of formula (3) from a ketone of formula(5).

[0163] In another process according to the invention, compounds offormula (1) where Z is a group (B) and R⁴ is a hydrogen atom or an alkylor —(CH₂)_(t)Ar group may be prepared by reacting a compound of formula(12)

[0164] with a phosphonate ester (R^(d)O)(OR^(e))P(O)CH(R⁵)(R⁶) [where Rdand Re, which may be the same or different is an alkyl, or aralkylgroup] in the presence of a base in a suitable solvent.

[0165] Suitable bases include organometallic bases such asorganolithium, e.g. n-butyllithium, alkoxides, for example alkali metalalkoxides such as sodium ethoxide or sodium methoxide and a hydride suchas potassium hydride or sodium hydride. Solvents include ethers, e.g.diethylether or cyclic ethers such as tetrahydrofuran and alcohol, e.g.methanol or ethanol.

[0166] The phosphonate derivatives used in this reaction are eitherknown compounds or may be prepared by reacting a phosphiteP(ORd)₂(OR^(e)) with a compound R⁵CHR⁶Hal [where Hal is a halogen atom,for example a bromine atom] using conventional methods.

[0167] Intermediates of formula (12) where R⁴ is a hydrogen atom may beprepared by reacting a halide of formula (13)

[0168] where Hal is a halogen atom, e.g. a bromine or chlorine atom withan organometallic reagent using the same reagents and conditionsdescribed above for the preparation of intermediates of formula (9)where W^(a) is —CHO from intermediates of formula (8).

[0169] Intermediates of formula (2) where ═W— is =N— and R⁴ is H may beprepared from an acid of formula (14)

[0170] using the conditions described above for the preparation of anintermediate of formula (5) from an acid of formula (6).

[0171] Intermediates of formula (14) where L is X^(a)Alk′Ar′ or X^(a)R′and —X^(a) is —O—, —S— or —NH—, may be prepared by reacting a halide offormula (15)

[0172] where Hal is a halogen atom, e.g. a bromine, chlorine or iodineatom with a compound ArAlk′X^(a)H, where —X^(a) is —O—, —S— or —NH— inthe presence of a base.

[0173] Bases used in this reaction include a hydride, such as sodiumhydride, or an organometallic base such as butyllithium in a solvent,such as an amide, for example dimethylformamide at a temperature fromroom temperature to above, e.g. 80%.

[0174] Intermediates of formula (15) may be prepared by reacting theknown amine of formula (16)

[0175] with nitrous acid (made in situ by reacting sodium nitrite withan acid, for example sulphuric acid or hydrobromic acid) to produce thediazonium salt. This in turn may be reacted with a haloacid, e.g.hydrobromic, hydrochloride or hydriodic acid if necessary in thepresence of the corresponding copper (I), halide (CuBr or Cul) orhalogen Br₂, Cl₂ or I₂.

[0176] Intermediates of formula (13) where L is a —C(R)═C(R¹)(R²) groupmay be prepared by coupling a compound of formula (17)

[0177] where Hal is a halogen atom, e.g. a bromine atom with aphosphonium salt (R¹)(R²)CHP(D)₃Hal as described below for thepreparation of compounds of formula (1) from intermediates of formula(19).

[0178] Intermediates of formula (12) where R⁴ is an alkyl or—(CH₂)_(t)Ar group may be prepared by reaction of the correspondingcompound of formula (12) where R⁴ is a hydrogen atom with anorganometallic reagent, followed by oxidation, as described previouslyfor the preparation of intermediates of formula (9) where W^(a) is—C(O)R⁴ where R⁴ is an alkyl or aryl group (CH₂)_(t)Ar fromintermediates of formula (9) where R⁴ is a hydrogen atom.

[0179] In another process for the preparation of compounds of formula(1) where Z is the group (B), an intermediate of formula (18)

[0180] may be coupled in a Heck reaction with an organopalladiumcompound derived from a compound R⁵Hal [where Hal is a halogen atom suchas a bromine atom] and a palladium salt such as palladium acetate in thepresence of a phosphine such as tri-o-tolylphosphine and a base such astriethylamine at an elevated temperature and pressure.

[0181] Intermediate alkenes of formula (18) may be obtained by reactionof a corresponding intermediate of formula (12) using a Wittig reactionemploying a phosphonium salt such as methyltriphenylphosphonium bromidein the presence of a base such as n-butylithium and an inert solventsuch as tetrahydrofuran at, for example, 0° C. to ambient temperature.

[0182] Intermediates of formula (3) where L² is a -Alk′L³ group in whichAlk′ is an alkenylene chain —C═C-Alk′- and L³ is a hydroxyl group may beprepared by coupling a compound of formula (19)

[0183] where R is a hydrogen atom or an alkyl group such as a methylgroup, with an olefination agent.

[0184] Particular examples of olefination agents include phosphoniumsalts such as compounds HOAlk′P(D)₃Hal [where the hydroxyl group mayneed to be protected using conventional protecting group] where Hal is ahalogen atom, such as a bromine atom and D is an optionally substitutedalkyl, e.g. methyl, or aryl, especially phenyl group; phosphoranesHOAlk° C.=P(D)₃; phosphonates (DO)₂P(O)Alk′OH; or silane derivatives,for example compounds of formula (D)₃SiAlk′OH e.g. trialkylsilanes suchas (CH₃)₃SiAlk′OH.

[0185] Intermediates of formula (19) where R is an alkyl group, may beprepared by reacting an intermediate of formula (19) where R is ahydrogen atom with an organometallic reagent, such as an alkyllithium oran organomagnesium RMgHal, using the conditions described above,followed by oxidation of the resulting alcohol, using an oxidisingagent, e.g. manganese dioxide.

[0186] Intermediates of formula (19) where R is a hydrogen atom may beprepared by deprotecting a protected aldehyde of formula (20)

[0187] where P¹ is a protected aldehyde group, e.g. a dioxanyl group,using acid hydrolysis e.g. by reaction with trifluoroacetic acid orp-toluene sulphonic acid, in the presence of a solvent, e.g. acetone, ora mixture of solvents, e.g. chloroform and water.

[0188] Intermediates of formula (20) may be prepared by protecting analdehyde or ketone of formula (19) with an aldehyde or ketone protectinggroup, using for example a suitable diol, e.g. 1,3-propanediol, in thepresence of an acid catalyst, e.g. 4-toluene sulphonic acid, in asolvent, such as an aromatic solvent, e.g. toluene, at an elevatedtemperature.

[0189] In general, this reaction may be used when it is desired toprotect an aldehyde in any intermediate described herein.

[0190] Compounds of formula (1) where L is a group —C(R)═C(R¹)(R²) orAlk′Ar′ where Alk′ is an alkenylene chain —C═C-Alk′ may be prepared froman intermediate of formula (19) using an appropriate olefination agent.

[0191] Particular examples of olefination agents include phosphoniumsalts such as compounds (R¹)(R²)CHP(D)₃Hal or Ar′Alk′P(D)₃Hal where Halis a halogen atom, such as a bromine atom, and D is an optionallysubstituted alkyl, e.g. methyl, or aryl, especially phenyl, group;phosphoranes (R¹)(R²)C═P(D)₃ or Ar′Alk′=P(D)₃; phosphonates(DO)₂P(O)CH(R¹)(R²) or (DO₂)P(O)Alk′Ar′; or silane derivatives, forexample compounds of formula (D₃)SiC(R¹)(R²) or (D₃)SiAlk′Ar′, e.g.trialkylsilanes such as (CH₃)₃SiC(R¹)(R²) or (CH₃)₃SiAlk′Ar′.

[0192] Bases for use in the above reaction include organometallic bases,for example, an organolithium compound such as an alkyllithium e.g.n-butyllithium, a hydride, such as sodium or potassium hydride or analkoxide, such as a sodium alkoxide, e.g. sodium methoxide.

[0193] The reaction may be performed in a suitable solvent, for examplea polar aprotic solvent, such as an alkyl sulphoxide, e.g. methylsulphoxide, an amide such as N,N-dimethylformamide orhexamethylphosphorous triamide; a non-polar solvent, such as an ether,e.g. tetrahydrofuran or diethyl ether or an aromatic solvent such asbenzene, toluene or xylene; or a polar protic solvent, such as analcohol, for example ethanol. Preferably the reaction is carried out ata low temperature, for example from around −78° C. to around roomtemperature.

[0194] The olefination agents used in this reaction are either knowncompounds or may be prepared from known starting materials usingreagents and conditions similar to those used to prepare the knowncompounds. For example, a phosphorane may be prepared in situ byreaction of a phosphonium salt with a base of the type described above.In another example, a phosphonate reagent may be prepared by reacting ahalide Alk′Hal with a phosphite (DO)₃P, as described in the Arbuzovreaction. Silane derivatives may be prepared by reaction of a halosilane(D)₃SiHal where Hal is a halogen atom, for example a chlorine atom, witha base, such as lithium diisopropylamide, in a solvent, such as anether, for example a cyclic ether, e.g. tetrahydrofuran, at lowtemperature, e.g. −10° C.

[0195] According to a further aspect of the invention, compounds offormula (1) where L is a group —C(R)═CH(R¹) and R¹ is an optionallysubstituted alkyl, alkenyl or alkenyl group may also be prepared byreaction of an intermediate of formula (19) with an organometallicreagent, followed by dehydration of the corresponding alcohol.

[0196] Examples of organometallic reagents include organolithium R¹Li ororganomagnesium R¹MgHal reagents. The reaction with the organo-metallicreagent may be performed in a solvent such as an ether, e.g. diethylether or for example a cyclic ether such as tetrahydrofuran, at a lowtemperature for example −10° C. to room temperature. The dehydration maybe performed using an acid, for example an organic acid such asp.toluene sulphonic acid or trifluoracetic acid, in the presence of abase, such as an amine, e.g. triethylamine.

[0197] In yet another process according to the invention, compounds offormula (1) wherein R³, R⁶ and R⁷ is each a hydrogen atom may beprepared by decarboxylation of an acid of formula (21):

[0198] The reaction may be carried out by treatment of the compound offormula (21) with a base, for example an inorganic base such as ahydroxide, e.g. sodium hydroxide in a solvent such as an alcohol, e.g.ethanol, at an elevated temperature e.g. the reflux temperature,followed by acidification of the reaction mixture to a pH of around pH4to around pH₆ using an acid such as an inorganic acid, e.g. hydrochloricacid, at an elevated temperature, e.g. the reflux temperature.

[0199] If desired, the acid of formula (21) may be generated in situfrom the corresponding ester or nitrite using the above reactionconditions, or by initial treatment with an acid.

[0200] Intermediates of formula (21) may be prepared by reacting acompound of formula (22)

[0201] [where R¹⁵ is an ester of an acid —CO₂H (e.g. an alkyl ester suchas an ethyl ester) or a nitrite —CN], with a Grignard reagent R⁴MgBr, inthe presence of a complexing agent, e.g. a copper (I) bromide-dimethylsulphide complex, or a copper (I) chloride, or with an organolithiumcompound, e.g. R⁴Li, in a solvent, e.g. tetrahydrofuran, at lowtemperature, e.g. around −40° C., followed by treatment with a base oran acid to yield the acid of formula (21). The Grignard and the lithiumreagents are either known compounds or may be prepared in a mannersimilar to that used to synthesise the known compounds.

[0202] Compounds of formula (22) may be obtained by reacting an adehydeof formula (12) with an ester or nitrile R⁵CH₂R¹⁵ in an acid solvent,such as acetic acid, at an elevated temperature, for example the refluxtemperature, in the presence of a base, such as ammonium acetate.

[0203] In a further process according to the invention a compound offormula (1) wherein R³, R⁶ and R⁷ is each a hydrogen atom and R⁵ is aheteroaryl group may be generally prepared by cyclisation of a compoundof formula (23):

[0204] where R¹⁶ is a carboxylic acid [—CO₂H] group or a reactivederivative thereof; or a nitrile [—CN] or an imine salt with abifunctional reagent W¹R^(5a)W² and, where necessary, a compoundR^(5b)W³ [where W¹, W² and W³, which may be the same or different, iseach a reactive functional group or a protected derivative thereof; andR^(5a) and R^(5b)are components of the heteroaryl group R⁵ such thatwhen added together with W¹, W² and W³ to the group R¹⁶ in compounds offormula (23) the resulting group -RW¹ R^(5a)W² or —RW¹ R^(5a)W²R^(5b)W³constitutes the heteroaryl group R^(5].)

[0205] Reactive derivatives of carboxylic acids for use in this reactioninclude acid halides, (e.g. acid chlorides), amides, includingthioamides, or esters, including thioesters. Imine salts include forexample salts of formula [e.g. —C(OAlk)═NH₂+A⁻, where Alk is a C₁₋₄alkylgroup and A⁻ is a counterion e.g. a chloride ion].

[0206] In this general reaction the reactive functional groupsrepresented by W¹, W² or W³ may be any suitable carbon, nitrogen,sulphur or oxygen nucleophiles. Particular examples include simplenucleophiles such as carbanions [e.g. generated by the coupling of analkyl group with an organometallic compound], amino, thiol and hydroxylgroups.

[0207] In general, the cyclisation reaction will initially be performedin a solvent, for example an inert solvent such as a halocarbon, e.g.dichloromethane, an ether, e.g. a cyclic ether such as tetrahydrofuran,or a hydrocarbon, e.g. an aromatic hydrocarbon such as toluene, from alow temperature, e.g. around −70° C., to around the reflux temperature,where necessary in the presence of a base or a thiation reagent, e.g.Lawesson's reagent, followed if necessary by heating, to an elevatedtemperature, e.g. the reflux temperature.

[0208] Thus, in one particular example, compounds of formula (1) whereinR³, R⁶ and R⁷ is each a hydrogen atom and R⁵ is a benzothiazolyl,benzoxazolyl or benzimidazolyl group may be prepared by reaction of acompound of formula (19) where R¹6 is an acid halide, e.g. acidchloride, with a reagent W¹R^(5a)W² which is 2-aminothiophenol,2-hydroxyphenol, or 1,2-diaminobenzene respectively in the presence of abase e.g. an organic amine such as pyridine, in a solvent e.g. ahalocarbon such as dichloromethane, from around −70° C. to the refluxtemperature.

[0209] In another example of the general cyclisation process, a compoundof formula (23) where R¹⁶ is an acid halide as described above may bereacted with a compound WI R^(5a)W² which is a monoalkylmalonate, e.g.ethyl hydrogen malonate, followed by reaction with a compound R^(5b)W³which is hydrazine to give a compound of formula (1) wherein R³, R⁶ andR⁷ is each a hydrogen atom and R⁵ is a 5-hydroxypyrazolyl group.

[0210] In another variation of the cyclisation process, the halide offormula (23) may be reacted with a compound W¹R^(5a)W² which isBrMg(CH₂)₃[—O(CH₂)₂O—] followed by reaction in an acid solution with acompound R^(5b)W³ which is methylamine to yield a compound of formula(1) wherein R³, R⁶ and R⁷ is each a hydrogen atom and R⁵ is a N-methylpyrrole group.

[0211] In a further example of the cyclisation process, the acid halideof formula (23) may be reacted with a compound W¹R^(5a)W² which isH₂NNHCSNH₂ in an aromatic hydrocarbon such as toluene, at an elevatedtemperature, e.g. around 150° C., followed by treatment with a base,e.g. an inorganic base such as sodium bicarbonate to give a compound offormula (1) wherein R³, R⁶ and R⁷ is each a hydrogen atom and R⁵ is a1,2,4-triazolyl-5-thiolate group.

[0212] Intermediate compounds of formula (23) are particularly usefuland form a further aspect of the invention. Active derivatives of theacids of formula (23) and other compounds of formula (23) where R¹⁶ is anitrile or an imine salt may be prepared from the corresponding acids[where R¹⁶ is —CO₂H] using conventional procedures for convertingcarboxylic acids to such compounds, for example as described in theExamples hereinafter.

[0213] Acids of formula (23) [where R¹⁶ is —CO₂H] may be prepared byhydrolysing a diester of formula (24)

[0214] where A¹ is a C14alkyl group, e.g. an ethyl group, with a base,e.g. sodium hydroxide, in a solvent, e.g. dioxane, at an elevatedtemperature, e.g. the reflux temperature, followed by acidification atan elevated temperature.

[0215] Diesters of formula (24) may be prepared by reacting a diester offormula (24)

[0216] with an organometallic reagent, such as a Grignard reagent usingthe conditions described above for the preparation of alcohols offormula (1).

[0217] In yet another process according to the invention, a compound offormula (1) where Z is a group (C) may be prepared by coupling acompound of formula (25),

[0218] where E is a boronic acid —B(OH)2 or a tin reagent Sn(R)₃, inwhich R is an alkyl group, for example a methyl group, with a reagentZ-L⁴, where L⁴ is a leaving group, in the presence of a complex metalcatalyst.

[0219] Particular leaving groups L⁴ include for example halogen atoms,e.g. bromine, iodine or chlorine atoms and an alkyl sulphonate, such astrifluoromethanesulphonate.

[0220] Suitable catalysts include heavy metal catalysts, for examplepalladium catalysts, such as tetrakis (triphenylphosphine)palladium. Thereaction may be performed in an inert solvent, for example an aromatichydrocarbon such as toluene or benzene, or an ether, such asdimethoxyethane or dioxane, if necessary in the presence of a base, e.g.an alkali carbonate such as sodium carbonate, at an elevatedtemperature, e.g. the reflux temperature. In general, the metal catalystand reaction conditions may be selected, depending on the nature of thecompound of formula (25) and/or the compound Z-L⁴ from a range of knownalternatives for reactions of this type [see for example Miyaura, Netal, Synth. Comm. (1981), 11, 513; Thompson, W. J. and Gaudino, J., J.Org. Chem, (1984), 49, 5237 and Sharp, M. J. etal, Tetrahedron Lett.(1987), 28, 5093].

[0221] Intermediates Z-L⁴ are either known compounds or may be preparedfrom known starting materials by methods analogous to those used for thepreparation of the known compounds. Thus, for example, where it isdesired to obtain a compound Z-L⁴ where L⁴ is a halogen atom such asbromine or chlorine atom and this compound is not readily available,such a compound may be prepared by (1) treatment of the correspondingamine with t-butyl nitrite and anhydrous CuCl₂ or CuBr₂ at elevatedtemperature, or (2) with t-butyl thionitrite or t-butyl thionitrate andCuCl₂ or CuBr₂ at room temperature followed by reaction with anappropriate copper (I) halide such as cuprous chloride or bromide in anaqueous acid.

[0222] Intermediates of formula (25) may be prepared by halogen-metalexchange between a compound of formula (13) where Hal is a bromine atomand an organometallic agent such as n-butyl or t-butyllithium followedby reaction with a borate such as triisopropylborate or a tin reagent(R)₃SnX, where R is as described above and X is a halogen atom, such aschlorine atom, optionally at a low temperature e.g. around −70° C., in asolvent such as tetrahydrofuran.

[0223] According to another aspect of the invention, a compound offormula (1) where Z is a group (D) in which −Z¹ is —NR¹²C(O)— or—C(O)NR¹²— may be prepared by coupling a compound of formula (26)

[0224] where —A is a —CO₂H or —NHR¹² group,

[0225] or an active derivative thereof with a compoundR¹²NH(Alk)_(t)(X)_(n)Ar or Ar(X)_(n)(Alk)_(t)CO₂H or an activederivative thereof. Active derivatives of acids of formula (26) orAr(X)_(n)(Alk)_(t)CO₂H include, for example, acid anhydrides, or acidhalides, such as acid chlorides.

[0226] The coupling reaction may be performed using standard conditionsfor reactions of this type. Thus for example, the reaction may becarried out in a solvent, for example an inert organic solvent such asan ether, e.g. a cyclic ether such as tetrahydrofuran, an amide, e.g. asubstituted amide such as dimethylformamide, or a halogenatedhydrocarbon such as dichloromethane, at a low temperature, e.g. −30° C.to ambient temperature such as −20° C. to 0° C., optionally in thepresence of a base, e.g. an organic base such as an amine, e.g.triethylamine or a cyclic amine such as N-methylmorpholine. Where anacid of formula (17) or Ar(X)_(n)(Alk)_(t)CO₂H is used, the reaction mayadditionally be performed in the presence of a condensing agent, forexample a diimide such as N,N′-dicyclohexylcarbodiimide, advantageouslyin the presence of a triazole such as 1-hydroxybenzotriazole.Alternatively, the acid may be reacted with a chloroformate, for exampleethylchloroformate, prior to reaction with the amine.

[0227] Intermediate acids of formula (26) where A is a —CO₂H group maybe prepared by hydrolysis of a corresponding ester of formula (27)

[0228] where Alk^(a) is an alkyl group; by heating in the presence of abase, for example an alkali metal hydroxide such as lithium hydroxide ina solvent such as an alcohol, e.g. methanol.

[0229] Intermediates of formula (26) where A is a —NHR¹² group and R¹²is a hydrogen atom, may be prepared by hydrogenation of a correspondingnitro compound of formula (28)

[0230] using the reagents described below for the hydrogenation of acompound of formula (1) where —L is a —CH═C(R¹)(R²) chain to a compoundof formula (1) where —L is a —CH₂CH(R¹)(R²) chain.

[0231] Intermediates of formula (26) where A is a NHR¹² group in whichR¹² is an alkyl group may be prepared by alkylation of an intermediateof formula (26) in which R¹² is a hydrogen atom, using an alkyl halidee.g. an alkyl iodide in a solvent, such as an aromatic solvent, forexample benzene.

[0232] Intermediates of formulae (27) and (28) and the reagentsR¹²NH(Alk)_(t)(X)_(n)Ar and Ar(X)_(n)(Alk)_(t)CO₂H are known compoundsor may be prepared from known starting materials by methods analogous tothose used for the preparation of the known compounds.

[0233] In yet another aspect of the invention compounds of formula (1)where Z is a group(D) in which Z¹ is a —C≡C— chain and n and t is eachzero may be prepared by reacting a compound of formula (29)

[0234] with a reagent Ar(X)_(n)(Alk)_(t)L⁵ (where L⁵ is a leaving group)in the presence of a metal complex catalyst, and in a solvent

[0235] Examples of L⁵ leaving groups include halogen atoms such asbromine, iodine or chlorine atoms or alkyl triflate such astrifluoromethane sulphonate. Suitable solvents include for example anamine, for example a tertiary amine, e.g. triethylamine, a secondaryamine, e.g. dimethylamine or a primary amine e.g. n-butylamine.

[0236] Metal complex catalysts include palladium catalysts, such asPd(Hal)₂(PPh₃)₂ or Pd(PPh₃) 4 (where Hal is a halogen atom e.g. achlorine atom) in the presence of copper (I) iodide, at a temperaturefrom room temperature to an elevated temperature, e.g. the refluxtemperature. (Comprehensive organic synthesis, vol. 3., 531-541; Trost,Fleming. Pergamon Press, 1991).

[0237] Intermediates of formula (29) may be prepared by reacting adihalide of formula (30)

[0238] where Hal is a halogen atom, e.g. a bromine atom, with a basesuch as an organometallic base, for example an organolithium, e.g.n-butyllithium, in a solvent such as an ether, e.g. tetrahydrofuran ordiethylether, at a temperature from around −78° C. to room temperature.

[0239] Intermediates of formula (30) may be prepared by reacting analdehyde of formula (12) (where R⁴ is a hydrogen atom) with a reagentHal₂C═P(Ar¹)₃ (where Hal is a halogen atom, such as a bromine atom andAr¹ is an aryl group, such as phenyl or -tolyl), prepared in situ fromC(Hal)4 and P(Ar¹)₃ in the presence of a base, such a an organometallicbase, for example an organolithium, e.g. n-butyllithium).

[0240] In a futher aspect of the invention, compounds of formula (1)where Z is a group (D) in which Z¹ is a —NR¹²SO₂— or —SO₂NR¹²— group maybe prepared by reaction of a compound of formula (30)

[0241] where (a) W^(b) is a —NHR¹² group with a compoundAr(X)_(n)(Alk)_(t)SO₂Hal [where Hal is a halogen atom, e.g. a bromine orchlorine atom], if necessary in the presence of a base; or,

[0242] (b) W^(b) is a —SO₂Hal group with a compoundAr(X)_(n)(Alk)_(t)NHR¹² using the reagents and conditions described in(a) above.

[0243] Examples of bases used in this reaction include amine, such astertiary amine, for example triethylamine, in a solvent such as anether, for example a cyclic ether, e.g. tetrahydrofuran.

[0244] Compounds Ar (X)_(n)(Alk)_(t)NHR¹² and compounds of formula (30)where Wb is a —NHR¹² group are known compounds or may be prepared usingsimilar reagents and conditions to those used to prepare the knowncompounds.

[0245] Compounds of formula (30) where W^(b) is —SO₂Hal, may be preparedby reacting an intermediate halide of formula (13) with anorganometallic reagent, such as an organolithium, e.g. n-butyllithium ina solvent, such as an ether, e.g. tetrahydrofuran, at a low temperaturee.g. around −60° C. to −100° C. followed by reaction with sulphurylchloride, in a solvent, such as an aliphatic solvent, e.g. n-hexane, ata low temperature, e.g. around 0° C.

[0246] Compounds of formula (1) where L is a group —CH(R¹)(R²) where R²is a —CO₂H group may be prepared by reacting a compound of formula (31)

[0247] where Hal¹ is a halogen atom, such as a chlorine or a bromineatom, with a diazoalkane CH(R¹)N₂ to give the corresponding diazoketonederivative which is then treated with water and silver oxide or withsilver benzoate and triethylamine.

[0248] Intermediates of formula (31) may be prepared by oxidation of analdehyde of formula (19), using an oxidising agent, such as permanganateor chromic acid, to give the corresponding carboxylic acid which is thenreacted with a halide reagent, such as thionylchloride, phosphorouspentachloride or phosphorous pentabromide.

[0249] Compounds of formula (1) may also be prepared by interconvertingother compounds of formula (1). Thus, for example where Z is a group (A)in which R³ is a hydrogen atom may be prepared by hydrogenation of acompound of formula (1) where Z is a group (B).

[0250] The hydrogenation may be performed using for example hydrogen inthe presence of a catalyst. Suitable catalysts include metals such asplatinum or palladium optionally supported on an inert carrier such ascarbon or calcium carbonate; nickel, e.g. Raney nickel, or rhodium. Thereaction may be performed in a suitable solvent, for example an alcoholsuch as methanol or ethanol, an ether such as tetrahydrofuran ordioxane, or an ester such as ethyl acetate, optionally in the presenceof a base, for example a tertiary organic base such as triethylamine, atfor example ambient temperature.

[0251] Alternatively, the reaction may be accomplished by transferhydrogenation using an organic hydrogen donor and a transfer agent.Suitable hydrogen donors include for example acids, such as formic acid,formates, e.g. ammonium formate, alcohols, such as benzyl alcohol orethylene glycol, hydrazine, and cycloalkenes such as cyclohexene orcyclohexadiene. The transfer agent may be for example a transitionmetal, for example palladium or platinum, optionally supported on aninert carrier as discussed above, nickel, e.g. Raney nickel, ruthenium,e.g. tris (triphenylphosphine) ruthenium chloride or copper. Thereaction may generally be performed at an ambient or elevatedtemperature, optionally in the presence of a solvent, for example analcohol such as ethanol or an acid such as acetic acid.

[0252] In a second example of an interconversion process, compounds offormula (1) where Z is a group (A) in which R⁷ is an OR^(c) group whereR^(c) is an alkyl or alkenyl group, may be prepared by reacting acompound of formula (1) where Z is a group (A) in which R⁷ is a —OHgroup, with a reagent RC—OH, in the presence of an acid, such assulphuric acid.

[0253] In another example of an interconversion process, compounds offormula (1) where Z is a group (A) in which R⁷ is an OR^(c) group whereR^(c) is a carboxamido or thiocarboxamido group may be prepared byreaction of a compound of formula (1) where Z is a group (A) in which R⁷is a —OH group, with an isocyanate R^(c)N═C═O or an isothiocyanateR^(c)N═C═S in the presence of a base, such as sodium hydride, in asolvent, such as tetrahydrofuran. Compounds R^(c)N═C═O and R^(c)N═C═Sare known compounds or may be prepared using the reagents and conditionsused for the preparation of the known compounds. When R^(c)N═C═S is notavailable, a compound of formula (1) where R^(c) is a thiocarboxamidogroup may be prepared by interconverting a compound of formula (1) whereR^(c) is a carboxamido group using a thiation reagent, such asLawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-di-sulphide],in an aromatic solvent, such as xylene or toluene.

[0254] In a yet another example of an interconversion process, acompound of formula (1) where Z is a group (A) in which R³ is a fluorineatom may be prepared by reacting a compound of formula (1) where Z is agroup (A) in which R³ is a hydroxyl group, with a fluorinating reagent,such as diethylaminosulphur trifluoride (DAST), in a solvent, forexample a chlorinated solvent, e.g. dichloromethane, at a lowtemperature, e.g. around 0° C.

[0255] In a still further example of an interconversion process, acompound of formula (1) where Z is a group (A) in which R³ is an alkylgroup, may be prepared by alkylation of a compound of formula (1) whereZ is a group (A), and R³ is a hydrogen atom, with a reagent R³L³ using abase, for example n-butyllithium or lithium diisopropylamide. In thisprocess, R⁴ in the starting material is preferably an electronwithdrawing group.

[0256] In a still further example of interconversion process, a compoundof formula (1) where L is (X^(a))_(n)Alk′Ar′ or Alk′X^(a)Ar′ where Alk′is an alkylene chain, may be prepared by hydrogenation of a compound offormula (1) where Alk′ is an alkenylene or alkynylene chain, using forexample hydrogen in the presence of a metal catalyst, as described abovefor the hydrogenation of a compound of formula (1) where Z is a group(B) to give a compound of formula (1) where Z is the group A.

[0257] Compounds of formula (1) where Z is the group (B) may also beprepared by dehydrating a compound of formula (1) where Z is the group(A) and R³ is a hydroxyl group, by using an acid, e.g. trifluoroaceticacid, in the presence of a base, such as an amine, e.g. triethylamine,in a solvent, such as dichloromethane, at a low temperature, e.g. around−10° C.

[0258] Where it is desired to obtain a particular enantiomer of acompound of formula (1) this may be produced from a correspondingmixture of enantiomers using any suitable conventional procedure forresolving enantiomers.

[0259] Thus for example diastereomeric derivatives, e.g. salts, may beproduced by reaction of a mixture of enantiomers of formula (1) e.g. aracemate, and an appropriate chiral compound, e.g. a chiral acid orbase. Suitable chiral acids include, for example, tartaric acid andother tartrates such as dibenzoyl tartrates and ditoluoyl tartrates,sulphonates such as camphor sulphonates, mandelic acid and othermandelates and phosphates such as 1,1′-binaphthalene-2,2′-diyl hydrogenphosphate. The diastereomers may then be separated by any convenientmeans, for example by crystallisation and the desired enantiomerrecovered, e.g. by treatment with an acid or base in the instance wherethe diastereomer is a salt.

[0260] In another resolution process a racemate of formula (1) may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed above. N-oxides of compounds of formula (1) may be preparedfor example by oxidation of the corresponding nitrogen base using anoxidising agent such as hydrogen peroxide in the presence of an acidsuch as acetic acid, at an elevated temperature, for example around 70°C. to 80° C., or alternatively by reaction with a peracid such asperacetic acid in a solvent, e.g. dichloromethane, at ambienttemperature.

[0261] Salts of compounds of formula (1) may be prepared by reaction ofa compound of formula (1) with an appropriate acid or base in a suitablesolvent or mixture of solvents e.g. an organic solvent such as an ethere.g. diethylether, or an alcohol, e.g. ethanol using conventionalprocedures.

[0262] The following Examples illustrate the invention. In the Examples,the following abbreviations are used DME—ethylene glycol dimethyl ether;THF—tetrahydrofuran; CH₂Cl₂— dichloromethane; Et₂O—ether; EtOH—ethanol;RT—room temperature; DMF—N, N-dimethylformamide; EtOAc—ethyl acetate;MeOH—methanol.

[0263] Intermediates 1-6 were prepared as described in InternationalPatent Specification No. WO 94/14742.

[0264] Intermediate 1

[0265] 3-Cyclopentyloxy 4-methoxybenzaldehyde

[0266] Intermediate 2

[0267] (3-Cyclopentyloxy-4-methoxyphenyl)phenylketone

[0268] Intermediate 3

[0269](±)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-hydroxy-2-phenyl-ethyl]pyridine

[0270] Intermediate 4

[0271] (E) and (Z) isomers of4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethenyl] pyridine

[0272] Intermediate 5

[0273] (±)4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine

[0274] Intermediate 6

[0275] (i)(+)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine

[0276] (ii) (−)4-[2-(3-Cyclopentyloxy4-methoxyphenyl)-2-phenylethyl]pyridine

[0277] Intermediate 7

[0278] a) (R) 4-[2-(3-Hydroxy-4-methoxyphenyl)-2-phenylethyl]pyridine

[0279] Intermediate 6 (i) (430 mg) in dioxane/water (20 ml:lOml)containing concentrated H₂SO₄ (10 ml) was heated at 90° C. for 1 h. Thereaction mixture was cooled, neutralised with aqueous NaHCO₃ thenconcentrated in vacuo. The residue was partitioned between EtOAc (25 ml)and H₂O (15 ml), and the organic phase separated. The extract was washedwith brine (25 ml), dried (MgSO₄) and concentrated in vacuo. The residuewas recrystallised (EtOH) to afford the title compound (240 mg) as anoff-white crystalline solid m.p. 195-197° C. (Found: C, 78.66;H, 627; N,4.59. C₂₀H₁₉NO₂ requires C, 78.64;H, 6.18; N, 4.42%); δ_(H) (CDCl₃) 3.30(2H, d, J 8 Hz, CHCH ₂), 3.86 (3H, s, OMe), 4.13 (1H, t, J 8 Hz, CHCH₂),5.7 (1H, br s, OH, 6.63 (1H, dd, J 8.3 Hz, ArH para to OH), 6.71 (1H, d,J 8.3 Hz, ArH ortho to OMe), 6.80 (1H, d, J 2.2 Hz, ArH ortho to OH),6.93 (2H, dd, J 4.5, 1.5 Hz, pyridine H ₃, H ₅), 7.1-7.3 (5H, m, C₆H₅),and 8.37 (2H, dd, J 4.5, 1.5 Hz, pyridine H ₃, H ₆).

[0280] The following Intermediate was prepared in a manner similar toIntermediate 7a)

[0281] b) (E)-4-[2-(3-Hydroxy-4-methoxyphenyl)ethenyl]pyridine

[0282] From Intermediate 20 (8.0 g, 27.1 mmol) in toluene (200 ml) andp-toluenesulphonic acid H₂O (10.3 g, 54.2 mmol) under a nitrogenatmosphere. Recrystallisation (EtOH) gave the title compound (3.8 g) asan amorphous yellow solid. m.p. 196-199° C. (Found C, 73.73;H, 6.03; N,6.06. C₁₄H₁₃NO₂ requires C, 73.99;H, 5.77; N, 6.16%). δ_(H) (300 MHz;CDCl₃) 3.92 (3H, s, OCH ₃), 6.22 (1H, br s, OH), 6.86 (1H, d, H 8.3 Hz,ArH ₄), 6.86 (1H, d, J 16.2 Hz, HC═C (trans)), 7.01 (1H, dd, J 8.3, 2.1Hz, ArH ₆), 7.17-7.26 (2H, m, ArH ₂ and HC═C), 7.34 (2H, dd, J 4.6, 1.6Hz, pyridine H ₃, H ₅), and 8.55 (2H, t, J 4.6, 1.4 Hz, pyridine H ₂, H₆).

[0283] Intermediate 8

[0284] 2-Methoxy4(3-pyridyl)benzaldehyde

[0285] A mixture of 5-bromo-2-methoxybenzaldehyde (10.00 g, 1.82 mmol)and tetrakis (triphenylphosphine)palladium (0) (2.10 g, 1.82 mmol, 3.9mol %) in DME (filtered through A1₂O₃) (50 ml) was stirred at RT for0.25 h. Sodium carbonate (2M, 50 ml, 0.10mol %) and diethyl(3-pyridyl)borane (6.817 g, 46.36 mmol) were added, the mixture heatedto reflux for 5.5 h then allowed to stand at RT overnight. The darkbrown reaction mixture was partitioned between water (50 ml) and Et₂O(lOOml) and the organic layer separated and combined with two furtherEt₂O extracts (1×50 ml, 1×25 ml). The organic phase was extracted with2N hydrochloric acid (2×50 ml) then the aqueous extract was basifiedwith 3M NaOH and extracted with Et₂O (1×150 ml, 2×50 ml). The combinedorganic extract was washed with brine (50 ml), dried (Na₂SO₄),concentrated in vacuo then submitted to column chromatography [SiO2;Et₂O] to furnish the title compound (3.318 g) as a pale yellow solid(Found: C, 73.40;H, 5.20; N, 6.44. C₁₋₃H₁₁NO₂ requires C, 73.23;H, 5.20;N, 6.57%.)

[0286] Intermediate 9

[0287] 2-(S-Bromo-2-methoxyphenyl1,3-dioxane

[0288] A mixture of 5-bromo-2-methoxybenzaldehyde (52.3 g, 243 mmol),1,3-propanediol (30 ml, 31.69, 415 mmol), and 4-toluenesulphonic acid(0.3 g) in toluene (350 ml) was heated to reflux in a Dean—Starkapparatus for 20 h. The mixture was cooled to RT, washed with saturatedNaHCO₃ solution (100 ml), then the organic layer was separated andcombined with a CH₂Cl₂ solution (100 ml). The extract was washed (brine;50 ml), dried (Na₂SO₄), and concentrated in vacuo to give a brown oil(66.2 g). The crude product was distilled to afford the title compound(58.2 g) as a colourless viscous oil b.p. 115-120° C., 0.02 mmHg δ_(H)(80 MHz; CDCl₃) 1.2-1.5 (1H, br m, CH₂CHHCH₂), 1.9-2.4 (1H, m, CH₂CHHCH₂), 3.78 (3H, s, OMe), 3.6-4.4 (4H, m, CH ₂CH ₂CH₂), 5.76 (1H, s, OCH),6.67 (1H, d, J 8.8 Hz, ArH ortho to OMe), 7.33 (1H, dd, J 8.8, 2.3 Hz,ArH para to acetal), and 7.68 (1H, d, J 2.3 Hz, ArH ortho to acetal);mLz (El) 274 (44%), 273 (31), 272 (45), 271 (27), 216 (34), 215 (47),214 (35), 213 (44), 193 (34), 135 (22), and 87 (100).

[0289] Intermediate 10

[0290] 3-[2-(1,3-Dioxanyl)]-4methoxybenzaldehyde

[0291] n-BuLi (1,6M solution in hexane) (125 ml, 200 mmol, 1.06 equiv.)was added dropwise to a solution of Intermediate 9 (51.65 g, 189 mmol)in THF (250 ml) at below −65° C. After 3.5 h, DMF (20 ml, 258 mmol, 1.37equiv.) was added at below −60° C. The reaction mixture was allowed towarm to RT then poured into hydrochloric acid (0.05 M; 500 ml) andimmediately extracted with CH₂Cl₂ (500 ml, 2×150 ml). The extract waswashed (brine; 200 ml), dried (K₂CO₃), and concentrated in vacuo to givea pale yellow oil (44.0 g). The crude product was triturated with warmhexane (250 ml) to afford the title compound (38.75 g) as an off-whitecrystalline solid δ_(H) (80 MHz; CDCl₃) 1,3-1.6 (1H, br m, CH₂CHHCH₂),1.8-2.5 (1H, m, CH₂CHHCH₂), 3.89 (3H, s, OMe), 3.7-4.4 (4H, m, CH ₂CH₂CH₂), 5.82 (1H, s, OCH), 6.93 (1H, d, J 8.4 Hz, ArH ortho to OMe), 7.82(1H, dd, J 8.4, 2.2 Hz, ArH para to acetal), 8.12 (1H, d, J 2.2 Hz, ArHortho to acetal), and 9.84 (1H, s, CHO).

[0292] Intermediate 11

[0293] 3-[3-(1,3-Dioxan-2-methoxyphenyl]-2-(4-pyridyl)propenenitrile

[0294] A mixture of Intermediate 10 (15.0 g, 67.5 mmol) and4-pyridylacetonitrile hydrochloride (10.75 g, 69.5 mmol) was stirred atRT in a mixture of EtOH (300 ml) and NaOH solution (3M; 40 ml, 150mmol). After 1 h, the precipitate was collected by filtration, washedwith EtOH (50 ml), then Et₂O (25 ml) and dried in vacuo to afford thetitle compound (15.85 g) as a very pale yellow solid SH (80 MHz; CDCl₃)1,3-1.7 (1H, br m, CH₂CHHCH₂), 2.0-2.4 (1H, m, CH₂CHHCH₂), 3.90 (3H, s,OMe), 3.8-4.4 (4H, m, CH ₂CH₂CH ₂), 5.83 (1H, s, OCH), 6.95 (1H, d, J8.5 Hz, ArH ortho to OMe), 7.47 (2H, dd, J 4.6, 1.7 Hz, pyridine H ₃, H₅), 7.63 (1H, s, CH═C), 7.96 (1H, d, J 2.4 Hz, ArH ortho to acetal),8.20 (1H, dd, J 8.5, 2.4 Hz, ArH para to acetal), and 8.61 (2H, dd, J4.6, 1.7 Hz, pyridine H ₂, H ₆).

[0295] Intermediate 12

[0296] 5-Bromo-2-methoxybenzylidenecyclopentane

[0297] n-BuLi (1.6M solution in hexane) (72.5 ml, 116 mmol) was addeddropwise at 0° C. to a solution of cyclopentyltriphenylphosphoniumbromide (45.8 g, 111 mmol) in THF (300 ml). The red solution was stirredat 0° C. for 0.5 h then treated with a solution of5-bromo-2-methoxybenzaldehyde (23.5 g, 109 mmol) in THF (150 ml). Thereaction mixture was stirred at RT overnight, concentrated in vacuo,then partitioned between CH₂Cl₂ (250 ml) and water (150 ml). The organicphase was separated and combined with further CH₂Cl₂ extracts (2×50 ml).The organic phase was washed (brine; 50 ml), dried (Na₂SO₄), andconcentrated in vacuo. The residue was subjected to chromatography(SiO₂; CH₂Cl₂) to afford the title compound (24.6 g), as a colourlessoil δ_(H) (80 MHz; CDCl₃) 1.6-1.9 (4H, br m, CH₂(CH ₂)₂), 2.3-2.6 (4H,br m, CH ₂(CH₂)₂CH ₂), 3.76 (3H, s, OMe), 6.4-6.5 (1H, br m, CH═C), 6.65(1H, d, J 8.5 Hz, ArH ortho to OMe), 7.18 (1H, dd, J 8.5, 2.4 Hz, ArHoara to olefin), and 7.39 (1H, d, J 2.4 Hz, ArH ortho to olefin).

[0298] Intermediate 13

[0299] 5-Formyl-2-methoxbenzylidenecyclopentane

[0300] n-BuLi (1.6M solution in hexane) (22 ml, 27.7 mmol, 1.1 equiv)was added dropwise at below −70° C. to a solution of Intermediate 12(6.81 g, 25.5 mmol) in THF (50 ml). The resulting orange solution wasstirred for a further 0.5 h then DMF (3.0 ml, 39 mmol, 1.5 equiv) wasadded at below −60° C. The reaction mixture was allowed to warm to RT,stirred for 1 h, then treated with hydrochloric acid (10%; 100 ml).After 1 h, the mixture was extracted with CH₂Cl₂ (150 ml, 2×50 ml). Theextract was washed (brine; 50 ml), dried (Na₂SO₄), and concentrated invacuo to give a yellow oil (7.0 g). The crude product was subjected tochromatography (SiO₂; Et₂O-hexane, 1:3) to afford the title compound(4.58 g) as a colouriess oil δ_(H) (80 MHz; CDCl₃) 1.6-1.9 (4H, br m,CH₂(CH ₂)₂), 2.4-2.65 (4H, br m, CH ₂(CH₂)₂CH ₂), 3.88 (3H, s, OMe),6.45-6.6 (1H, br m, CH═C), 6.89 (1H, d, J 8.6 Hz, ArH ortho to OMe),7.59 (1H, d, J 2.2 Hz, ArH ortho to olefin), 7.75 (1H, dd, J 8.6, 2.2Hz, ArH para to olefin), and 9.81 (1H, s, CHO).

[0301] Intermediate 14

[0302] 2-[2-Methoxy-5-(phenylhydroxymethyl)]-1,3-dioxane

[0303] n-BuLi (1.6M solution in hexane) (115 ml, 184 mmol) was addeddropwise at ca −70° C. to a solution of Intermediate 9 (50.3 g, 184mmol) in THF (1000 ml). A solution of benzaldehyde (20.5 g, 193 mmol) inTHF (100 ml) was added dropwise at ca −70° C. and the reaction mixtureallowed to warm to RT over 3 h. The mixture was quenched with 10%aqueous NH₄Cl solution (200 ml) and the organic layer separated andcombined with EtOAc extracts (3×100 ml). The extract was dried (MgSO₄)and concentrated in vacuo to afford the title compound (61.0 g) as apale yellow crystalline solid. δ_(H) (CDCl₃) 1.47 (1H, br d, J ca 13 Hz,CH₂CHCH₂), 2.15-2.35 (2H, complex m, CH₂CHCH₂+OH), 3.82 (3H, s, OMe),3.99 (2H, ca. t, J ca. 11 Hz, CHCH₂CH), 4.23 (2H, dd, J ca. 11.4 Hz,CHCH₂CH), 5.81 (1H, s, ArCH), 5.85 (1H, s, ArCH), 6.83 (1H, d, J 8.6HZ,ArH ortho to OMe), 7.2-7.4 (6H, m, C₆ H ₅+ArH para to dioxolane), and7.68 (1H, d, J 2.3 Hz, ArH ortho to dioxolane).

[0304] Intermediate 15

[0305] [3-(2-Dioxan-1,3-yl)4methoxy1benzophenone

[0306] A mixture of Intermediate 14 (60.0 g, 200 mmol) and manganesedioxide (174 g, 2.0 mol) in CH₂Cl₂ (1000 ml) was stirred at RT for 18 h.The reaction mixture was filtered through Celite and the filtrateconcentrated in vacuo. The residue was recrystallised from diisopropylether-toluene to afford the title compound (41.0 g) as a white solid.δ_(H) (CDCl₃) 1.41 (1H, br d, J 13.5 Hz, CH₂CHCH₂), 2.1-2.3 (1H, complexm, CH₂CHCH₂), 3.93 (3H, s, OMe), 3.99 (2H, dt, J 2.1, 12.3 Hz, CHCH₂CH),4.23 (2H, dd, J 4.5, 11.5 Hz, CHCH₂CH), 5.87 (1H, s, ArCH), 6.94 (1H, d,J 8.6HZ, ArH ortho to OMe), 7.4-7.6 (3H, m, meta and para C₆H₅), 7.75(2H, d, J 8.4 Hz ortho C₆H₅), 7.84 (1H, dd, J. 2.3, 8.6 Hz, ArH para todioxane), and 8.15 (1H, dd, J 2.3 Hz, ArH ortho to dioxane).

[0307] Intermediate 16

[0308] (±)-1-{3-[2-(1,3-Dioxanyl)]-methoxyphenyl}-1-phenyl-2-(4-pyridyl)ethanol

[0309] n-BuLi (2.5M solution in hexane) (55.6 ml, 139 mmol, 1.05equiv.)was added to a solution of 4-methylpyridine (11.9 ml, 133 mmol) in THF(500 ml) at −70° C. The mixture was allowed to stir at −70° C. for 0.5 hthen a solution of Intermediate 15 (40.0 g, 133 mmol) in THF (250 ml)was added dropwise and allowed to warm to RT overnight. The reactionmixture was quenched with 10% aqueous NH₄Cl solution (lOOml) andextracted with CH₂Cl₂ (300 ml, 100 ml). The extract was separated, dried(Na₂SO₄), and concentrated in vacuo. The residue was recrystallised fromEtOAc to afford the title compound (28.9 g) as a white crystalline solidδ_(H) (CDCl₃) 1.41 (1H, br d, J 13.5 Hz, CH₂CHCH₂), 2.15-2.25 (1H,complex m, CH₂CHCH₂), 2.4 (1H, br s, OH), 3.54 (1H, d, J 13.1 Hz,pyridine CH),3.62 (1H, d, J 13.1 Hz, pyridine CH), 3.82 (3H, s, OMe),3.99 (2H, dt, J 2.1, 12.3 Hz, CHCH₂CH), 4.23 (2H, dd, J 5.1,10.7 Hz,CHCH₂CH), 5.84 (1H, s, ArCH), 6.75-6.85 (3H, m, ArH meta/para to dioxane+C₆H₅ para H), 7.15-7.35 (6H, m pyridine H ₃, H ₅+C₆H₅ ortho/meta H),7.76 (1H, d, J 2,3HZ, ArH ortho to dioxane), and 8.30 (1H, dd, J 1.5,4.5 Hz, pyridine H ₂, H ₆)

[0310] Intermediate 17

[0311] (E, Z)4-{-2-[3-(2-Dioxan-1,3-yl-4methoxyphenyl]ethenyl}pyridine

[0312] Trifluoroacetic anhydride (11.3 ml, 80.2 mmol) was added dropwiseat ca. −10° C. to a solution of Intermediate 16 (28.59 g, 72.9 mmol) andtriethylamine (15.2 ml, 109.3 mmol) in CH₂Cl₂ (500 ml). The reactionmixture was stirred at −10° C. for 0.5 h then quenched with 10% aqueoussodium carbonate solution (250 ml). The organic layer was separated andcombined with further CH₂Cl₂ extracts (3×50 ml), then dried (Na₂SO₄) andconcentrated in vacua. The residue was subjected to chromatography(SiO₂; 5% MeOH CH₂Cl₂) to afford the title compound (20.0 g) as a yellowsolid. δ_(H) (CDCl₃) (′Hnmr indicates a 3:1 mlxture of isomers; data formajor isomer, possibly (E)—, presented) 1.43 (1H, br d, J 12.6 Hz,CH₂CHCH₂), 2.15-2.35 (1H, complex m, CH₂CHCH₂), 3.84 (3H, s, OMe), 4.01(2H, ca. t, J 11.5 Hz, CHCH₂CH), 4.26 (2H, dd, J 4.9, 11.5 Hz, CHCH₂CH),5.88 (1H, s, ArCH), 6.77 (1H, d, J 8.6 Hz, ArH ortho to OMe), 6.81 (2H,d, J 5.8 Hz, pyridine H ₃, H ₅), 6.85 (1H, s, C═CH), 7.03 (1H, dd, J2.3, 8.6 Hz, ArH para to dioxane), 7.1-7.2 (2H, m, C₆H₃ H ₂), 7.3-7.35(3H, m, C₆ H ₃H₂), 7.83 (1H, d, J 2.4 Hz, ArH ortho to dioxane) and 8.30(2H, d, J 5.8 Hz, pyridine H ₂, H ₆)

[0313] Intermediate 18

[0314] 2-Methoxy-5-yl-phenyl-2-(4-pyridyl)ethyl]benzaldehyde

[0315] A solution of Intermediate 17 (17.5 g, 46.8 mmol) in THF-MeOH(5:1; 1200 ml) containing 10% Pd/C (0.5 g) was hydrogenated at RT over 1h. The reaction mixture was filtered through Celite and thenconcentrated in vacuo. The crude alkane (15.0 g) in THF (750 ml) and 10%hydrochloric acid (75 ml) was vigorously stirred at RT for 0.5 h, thenquenched with aqueous NaHCO₃ (2M; 100 ml). The organic solvent wasremoved in vacua and the aqueous phase extracted with EtOAC (3×100 ml).The extract was dried (MgSO₄) and concentrated in vacuo to afford thetitle compound (12.6 g). δ_(H) (CDCl₃) 3.34 (2H, d, J 8.0 Hz, CHCH₂pyridine), 3.87 (3H, s, OMe), 4.22 (1H, t, J 8.0 Hz, CHCH₂pyridine),6.87 (1H, d, J 8.6 Hz, ArH ortho to OMe), 6.92 (2H, d, J 6.0 Hz, H ₂, H₆ of C₆H₅), 7.1-7.3 (5H, m, pyridine H ₃, H ₅+H ₃, H ₄, H ₅ of C₆H₅),7.32 (1H, dd,J 2.4, 8.6 Hz, ArHpara to CHO), 7.74 (1H, d, J 2.4 Hz, ArHortho to CHO), 8.38 (2H, ca. d, J 4.5 Hz, pyridine H ₂, H ₆) and 10.42(1H, s, ArCHO).

[0316] Intermediate 19

[0317] (±)4-[2-(3-Cyclopentyloxy 4methoxyphenyl)-2-hydroxyethylpyridine

[0318] The title compound was prepared as described in the InternationalPatent Application No. WO94/20446.

[0319] Intermediate 20

[0320] (E)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)ethenyl]pyridine

[0321] The title compound was prepared as described in the InternationalPatent Application No. WO94/20446.

[0322] Intermediate 21

[0323] 5-Phentylpentylbromide

[0324] To a stirred solution of 5-phenyl-1-pentanol (2.80 g, 17.07 mmol)in dry CH₂Cl₂ (80 ml) at 0° C. under a nitrogen atmosphere was addedPBr3 (4.62 g, 1.62 ml. 17.07 mmol). The mixture was stirred at RT for 34min and quenched cautiously with saturated NaHCO₃ solution (100 ml). Thelayers were separated and the aqueous layer extracted with CH₂Cl₂ (2×60ml). The combined organic extract was washed with water (80 ml), dried(MgSO₄)and the residue subjected to chromatography (SiO₂) to give thetitle compound (0.69 g) as a clear oil.

EXAMPLE 1

[0325] a) (R)-4-[2-(3-Benzyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine

[0326] Potassium tert-butoxide (180 mg, 1.57 mmol) was added to astirred solution of Intermediate 7 (400 mg, 1.31 mmol) in THF (15 ml)and DMF (5 ml). The mixture was stirred at RT for 0.25 h then treatedwith benzyl bromide (246 mg, 1.44 mmol). After 0.5 h at RT, the reactionmixture was quenched with water (5 ml) and concentrated in vacuo. Theresidue was partitioned between water (20 ml) and EtOAc (30 ml). Theorganic layer was separated and combined with further EtOAC extracts(2×30 ml). The extract was dried (MgSO₄) and concentrated in vacuo togive a pale brown oil which was subjected to chromatography (SiO₂;EtOAc-hexane, 17:3) to afford the title compound (434 mg) as acolourless oil SH (CDCl₃) 3.18 (1H, dd, J 13.6, 8.4 Hz, CHCH _(A)H_(B)),3.25 (1H, dd, J 13.6, 7.4 Hz, CHCH_(A) H _(B)), 3.84 (3H, s, OMe), 4.09(1H, t, J 7.9 Hz, CHCH_(A)H_(B)), 5.08 (2H, S, OCH₂), 6.58-6.8 (3H, m,C₆ H ₃), 6.82 (2H, dd, J 4.5,1.6 Hz, pyridine H ₃, H ₅), 7.05-7.4 (10H,m, 2×C₆ H ₅), and 8.35 (2H, dd, J 4.5,1.6 Hz, pyridine H ₂,H₆).

[0327] The following Example was prepared in a manner similar tocompound of Example 1a).

[0328] b) 4-{2-(R)[4-Methoxy3-(phenylpentloxy)phenyl]-2-phenylethyl}pyridine

[0329] From Intermediate 7a) (0.29 g, 0.95 mmol) in THF (5 ml) and DMF(3 ml), potassium t-butoxide (0.12 g, 1.04 mmol) and5-phenylbromopentane (0.26 g, 1.14 mmol) in THF (5 ml). Chromatography(SiO₂; EtOAc-hexane, 1:1) gave the title compound (0.339) as a clearcolourless oil. (Found C, 82.16;H, 7.38; N, 3.06. C₃₁H₃₃NO2 requires C,82.45;H, 7.37; N, 3.10%) δ_(H) (300 MHz: CDCl₃) 1.40-1.85 (6H, m, (CH₂)₃), 2.63 (2H, t, J 7.6 Hz, C₆H₅CH ₂), 3.31 (2H, d, J 7.9 Hz, CH ₂pyridine), 3.81 (3H, s, OCH₃), 3.90 (2H, dt, J 6.8, 1.6 Hz, OCH ₂), 4.15(1H, t, J 9 Hz, CH₂CH), 6.65 (1H, d, J 1.8 Hz, ArH ₂), 6.7-6.8 (2H, m,ArH), 6.92 (2H, dd, J 4.6, 1.4 Hz, pyridine H ₃, H ₅), 7.15-7.30 (10H,m, 2×C₆ H ₅), and 8.38 (2H ,dd, J 4.5, 1.5 Hz, H ₂, H ₆, pyridine).

[0330] c) (E)-4-[4-Methoxy-3-(5-phenylpentyloxy)phenylethenyl]pyridine

[0331] From Intermediate 7b) (0.68 g, 3.0 mmol) potassium t-butoxide(0.40 g, 3.6 mmol) and Intermediate 21 (0.68 g, 3.0 mmol).Chromatography (SiO₂; EtOAc-hexane, 3:1) gave a slightly off-white solid(0.874 g). A small portion (0.34 g) was recrystallised(diisopropylether; 9 ml) to give the title compound (0.312 g) as anamorphous white solid (0.312 g). m.p. 98-100° C. (Found C, 80.31;H,7.27; N, 3.56. C₂₅H₂₇NO₂ requires C, 80.40;H, 7.29; N, 3.7%). δ_(H) (300MHz; CDCl₃) 1.5-2.0 (6H, m, (CH ₂)₃), 2.67 (2H. t. J. 7.7 Hz, ArCH ₂),3.89 (3H, s, OCH ₃), 4.07 (2H, t, J 6.8 Hz, OCH ₂), 6.86 (1H, d, J16.3,HC═C), 6.88 (1H, d, J 8.9 Hz, ArH), 7.07-7.31 (6H, m, ArH andHC═C), 7.33 (2H, dd, J 4.6, 1.5 Hz, pyridine H ₃, H ₅) and 8.55 (2H, dd,J 4.6,1.5 Hz pyridine H ₂,H ₆).

EXAMPLE 2

[0332] a) (R)-4-[2-(4-Methoxy-3-(3-thienyloxy)phenyl)-2-phenylethyl]pyridine

[0333] A mixture of Intermediate 7a) (500 mg, 1.64 mmol), anhydrouspotassium carbonate (450 mg, 3.28 mmol) and 3-bromothiophene (3.48 g,21.3 mmol) in pyridine (4 ml) was heated to Ca 90° C. Copper (II) oxide(330 mg, 4.1 mmol) was added and the reaction mixture heated to refluxfor 52 h. CH₂Cl₂ (20 ml) was added to the cooled reaction mixture whichwas then filtered. The filtrate was concentrated in vacuo and theresidue subjected to chromatography (SiO2; EtOAc-hexane, 17:3) to affordthe title compound (315 mg), as a colourless oil. (Found C, 74.15;H,5.40; N, 3.50. C₂₄H₂₁NO₂S requires C, 74.39;H, 5.46; N, 3.61%) δ_(H)(CDCl₃) 3.24 (1H, dd, J 13.6, 8.5 Hz, CHxCH _(A)H_(B)), 3.30 (1H, dd, J13.6, 7.4 Hz, CHxCH_(A) H _(B)), 3.81 (3H, s, OMe), 4.14 (1H, t, J ca.8.0 Hz, CHxCH_(A)H_(B)), 6.28 (1H, dd, J 3.3, 1.5 Hz, thiophene H), 6.74(1H, dd, J 5.2, 1.5 Hz, thiophene H), 6.8-6.95 (5H, m), 7.1-7.3 (6H, m),and 8.39 (2H, br s, pyridine H ₂, H ₆).

[0334] The following Examples were prepared in a manner similar tocompound of Example 2a).

[0335] b) 4-{2-(R)-r3-(4-Biphenyloxy)4methoxyphenyl)-2-phenyl]ethyl}pyridine

[0336] From Intermediate 7a) (0.4 g, 1.131 mmol), anhydrous potassiumcarbonate (0.36 g, 2.62 mmol), 4-bromobiphenyl (0.4 g, 1.70 mmol) andcopper (II) oxide (0.26 g, 3.3 mmol). Chromatography (SiO2;EtOAc-hexane, 1:1 then 7:3) gave the title compound (0.383 g) as a clearcolourless foamy oil. (Found C, 83.40;H, 5.89; N, 3.03. C₃₂H₂₇NO₂requires C, 83.92;H, 5.95; N, 3.06%). δ_(H) (300 MHz; CDCl₃) 3.25 (1H,dd, J 13.6, 8.5 Hz, pyridine CH_(A) H _(B)), 3.25 (1H, dd, J 13.6, 7.5Hz, pyridine CH _(A) H _(B)) 3.80 (3H, s, OCH ₃), 4.16 (1H, t, C6H₃CH),6.85-7.0 (7H, m, ArH, pyridine H ₃, H ₅), 7, 15-7.6 (12H, m, ArH) and8.40 (2H, br s, pyridine H ₂, H ₆).

[0337] c) 4-[2-(R)-(4-Methoxy-3-phenyloxyphenyl)-2-phenylethyl]pyridine

[0338] From Intermediate 7a) (0.4 g, 1.31 mmol), anhydrous potassiumcarbonate (0.36 g, 2.62 mmol), bromobenzene (2.98 g, 2.0 ml, 19 mmol)and copper (11) oxide (0.26 g, 3.3 mmol). Chromatography (SiO₂;EtOAc-hexane, 17:3) gave the title compound (0.433 g) as a clear oil.(Found C, 81.45;H, 5.97; N, 3.48. C₂₆H₃₂NO2 requires C, 81.86;H, 6.08;N, 3.67%). δ_(H) (300 MHz; CDCl₃) 3.24 (1H, dd, J 13.6, 8.7 Hz, pyridineCH_(A) H _(B)), 3.29(1H, dd, J 13.6, 7.4 Hz, pyridine CH _(A)H_(B)),3.78 (3H, s, OCH ₃), 4.14 (1H, t, J 7.9 Hz, CH₂CH), 6.80-6.94 (7H, m,ArH, pyridine H ₃, H ₅), 7.00-7.06 (1H, m, ArH), 7,15-7.3 (7H, m, ArH)and 8.39 (2H, dd, J 4.5, 1.6 Hz, pyridine H ₂, H ₆).

EXAMPLE 3

[0339](2R)-4-[2(3-((2RS)exo-Bicyclo[2.2.1]hept-2-yloxy)4-methoxyphenyl)-2-phenylethyl]pyridine

[0340] Diethylazodicarboxylate (522 mg, 3.0 mmol) was added to a mixtureof Intermediate 7a) (610 mg, 2.0 mmol), (+)-endo-2-norborneol (224 mg,2.0 mmol), and triphenylphosphine (787 mg, 3.0 mmol) in THF (5 ml) andthe mixture heated to reflux for 40 h. The reaction mixture was pouredinto saturated NaHCO3 solution (lOml) and extracted with CH₂Cl₂ (2×25ml). The extract was dried (Na₂SO₄), concentrated in vacuo, and thensubjected to chromatography (SiO2; Et₂O) to afford the title compound(256 mg) as a colourless oil. SH (CDCl₃) 1.0-1.75 (8H, m, norbornylH's), 2.2-2.4 (2H, br m, norbornyl H's), 3.25-3.4 (2H, m, CHCH ₂), 3.77(3H, s, OMe), 4.05 (1H, br d, J 5.6 Hz, OCH), 4.14 (1H, t, J 7.9 Hz,CHCH₂), 6.6-6.8 (3H, m, C₆H₃), 6.92 (2H, ca d, J 4.5 Hz, pyridine H ₃, H₅), 7.1-7.3 (5H, m, C₆ H ₅), 8.38 (2H, ca.d., J 4.5 Hz, pyridine H ₂, H₆); mLz (El) 399 (M ⁺, 8%), 307 (13), 305 (18), 213 (100), 152 (18), 95(51), 93 (19), and 67 (37).

EXAMPLE 4

[0341] a) 3-(3-Cyclopentylidenyl-4-methoxyphenyl)pyridine hydrochloride

[0342] To a solution of cyclopentyl triphenylphosphonium bromide (3.66g, 8.9 mmol) in THF (50 ml) was added dropwise n-BuLi (1.6M in hexane)(5.6 ml, 9.0 mmol) at 0° C. The red solution was stirred and left towarm up to RT for 1 h then treated with a solution of Intermediate 8(1.9 g, 8.9 mmol) in THF (25 ml) at 0° C. After stirring for 1 h at RTthe reaction mixture was quenched with water (50 ml) and extracted withCH₂Cl₂ (1×75, 1×50, 1×25 ml). The extract was washed (brine), dried(Na₂SO₄) and concentrated in vacua to give a colourless syrup whichcrystallised to give a white solid. Purification by columnchromatography [SiO₂; EtOAc] furnished the title compound free base(1.80 g) as a white solid.

[0343] A portion of the free base (388 mg) was treated with ethanolicHCl and diluted with a little Et₂O. The precipitate was decanted, washed(Et₂O) and dried in vacua to furnish the title compound (420 mg) as apale yellow solid (Found: C, 71.56;H, 6.68; N, 4.74. C₁₈H₁gNO. HClrequires C, 71.63;H, 6.68; N, 4.64%). δ_(H) (80 MHz; CDCl₃) 1.6-1.9 (4H,br m, CH₂(CH ₂)₂CH₂), 2.4-2.65 (4H, br m, CH ₂(CH₂)₂CH ₂), 3.89 (3H, s,OMe), 6.5-6.6 (1H, br m, HC═C), 6.97 (1H, d, J 8.6 Hz, ArH ortho toOMe), 7.40 (1H, dd, J. 8.6, 2.2 Hz, ArH para to C═C), 7.53 (1H, d J 2.2Hz, ArH ortho to C═C), 7.9 (1H, dd, J. 5.6, 8.3 Hz, pyridine H ₅),8.4-8.7 (2H, m, pyridine H ₄, H ₆) and 8.85 (1H, d, J 2.2 Hz, pyridine H₂).

[0344] b)4-[2-(3-Cyclopentylidenylmethyl4-methoxyphenyl)-2-phenyl-ethyl]pyridinehyrochloride hemihydrate

[0345] From n-BuLi (1,6M solution in hexane) (2.1 ml, 3.55 mmol, 1.06equiv), cyclopentyltriphenylphosphonium bromide (1.43 g, 3.46 mmol, 1.1equiv) in THF (30 ml) and Intermediate 18 (1.00 g, 3.15 mmol) in THF (20ml). Chromatography (SiO₂; 2% MeOH—CH₂Cl₂) afforded the title compoundfree base (420 mg). δ_(H) (CDCl₃) 1.6-1.8 (4H, br m, CH₂(CH ₂)₂CH₂),2.2-2.35 (2H, br m, CH(CH₂)2CH), 2.4-2.55 (2H, br m, CH(CH₂)₂CH), 3.22(2H, d, J 7.8 Hz, CHCH ₂ pyridine), 3.78 (3H, s, OMe), 4.17 (1H, t, J7.8 Hz, CHCH₂ pyridine), 6.51 (1H, ca. t, J 2.2 Hz, HC═CCH₂), 6.72 (1H,d, J 8.4 Hz, ArH ortho to OMe), 6.85-7.0 (3H, m, H of C₆H₃+pyridine H ₃,H ₅), 7.1-7.3 (6H, m, C₆ H ₅+H of C6H₃) and 8.38 (2H, ca. d, J 5.7 Hz,pyridine H ₂, H ₆).

[0346] The base (420 mg) was dissolved in Et₂O (5 ml) and treateddropwise with ethanolic HCl. The precipitated product was collected byfiltration and dried in vacua to afford the title compound as a whitesolid (Found: C, 75.23;H, 6.72; N, 3.11; C₂₆H₂₈NO. 0.5H₂O requires C,75.25;H, 7.04; N, 3.38%). δ_(H) (CDCl₃) 1.6-1.8 (4H, br m, CH₂(CH₂)₂CH₂), 2.2-2.35 (2H, br m, CH(CH₂)2CH), 2.4-2.55 (2H, br m,CH(CH₂)₂CH), 3.59 (2H, d, J 8.0 Hz, CHCH ₂ pyridine), 3.80 (3H, s, OMe),

[0347] 4.18 (1H, t, J 8.0 Hz, CHCH₂ pyridine), 6.51 (1H, ca. t, J 2.0Hz, CH═CCH₂), 6.73 (1H, d, J 8.4 Hz, ArH ortho to OMe), 6.87 (1H, dd, J2.2, 8.4 Hz, ArH para to olefin), 7.1-7.45 (6H, m, C₆ H ₅+ArH ortho toolefin), 7.46 (2H, ca. d, J ca. 6.4 Hz, pyridine H ₃, H ₅), and 8.50(2H, ca. d, J ca. 6.4 Hz, pyridine H ₂, H ₆); m/z (ESI) 370 (M ⁺+1-HCl,18%), 369 (M ⁺-HCl, 95), 277 (100), 178 (55), 165 (75), and 152 (45).

[0348] c)4-[2-(3-Cyclohexylidenylmethyl-4-methoxyphenyl)-2-phenyl-ethyl]pyridinehydrochloride

[0349] From Intermediate 18 (1.00 g, 3.15 mmol),cyclohexyltriphenylphosphonium bromide (1.47 g, 3.46 mmol, 1.1 equiv)and n-BuLi (1.6 M solution in hexane) (2.1 ml, 3.36 mmol, 1.07 equiv).The crude product was subjected to chromatography (SiO2; 2% MeOH—CH₂Cl₂)to afford the title compound free base (1.07 g).

[0350] A portion of the free base (400 mg) was dissolved in Et₂O (5 ml)and treated with ethanolic HCl to afford the title compound as a whitesolid (Found: C, 77.32;H, 7.15; N, 3.24. C₂₇H₃₀CINO requires C, 77.21;H,7.20; N, 3.34%). δ_(H) (CDCl₃) 1.4-1.75 (6H, br m, CH₂(CH ₂)₃CH₂),2.0-2.1 (2H, br m, CH(CH₂)₃CH), 2.2-2.3 (2H, br m, CH(CH₂)₃CH), 3.58(2H,d, J 8.0 Hz, CHCH ₂ pyridine), 3.78 (3H, s, OMe), 4.18 (1H, t, J 8.0 Hz,CHCH₂ pyridine), 6.15 (1H, ca. s, HC═CCH₂), 6.73 (1H, d, J 9.0 Hz, ArHortho to OMe), 6.85-6.95 (2H, m, ArH), 7.1-7.35 (5H, m, ArH), 7.46 (2H,d, J 5.8 Hz, pyridine H ₃, H ₅), and 8.50 (2H, d. J 5.8 Hz, pyridine H₂, H ₆); m/z (ESI) 384 (M ⁺+1-HCl, 37%), 383 (M ⁺-HCl, 85), 291 (100),178 (32), 165 (50), 152 (28) and 91 (33).

[0351] d)4-{2(R)-[3-(Phenyl-1,3-butedienyl)-4-methoxyphenyl]-2-phenylethyl}pyridine

[0352] From n-BuLi (1.6M solution in hexane) (1.2 ml, 2.93 mmol,1.05equiv).` cinnamyltriphenylphosphonium bromide (930.6 mg, 2.02 mmol)and Intermediate 9 (583.9 mg, 1.84 mmol). Chromatography (SiO₂;EtOAc-hexane, 1:1) gave the title compound.

EXAMPLE 5

[0353] a) 3-(3-Cyclopentylmethyl-4-methoxyphenyl) pyridinehydro-chloride

[0354] The compound of Example 4a) (485 mg) was hydrogenated over theweekend in EtOH (25 ml) in the presence of 5% Pd/C (50 mg). The reactionmixture was filtered through Celite and concentrated in vacuo to givethe title compound free base (464 mg) as a colourless oil.

[0355] The free base was dissolved in warm ethanolic HCl, precipitatedwith Et₂O, decanted and dried in vacuo to yield the title compound (485mg) as a white solid. (Found: C, 70.98;H, 7.31; N, 4.62. C₁₈H₂₁NO. HClrequires C, 71.16;H, 7.30; N, 4.61%). SH (80 MHz; CDCb) 1.5-1.8 ((H,v.br m, cyclopentyl H's), 2.67 (2H, d, J 6.8 Hz,CH ₂ cyclopentyl), 3.87(3H, s, OMe), 6.95 (1H, d, J 8.0 Hz, ArH ortho to OMe), 7.35-7.50 (2H,m, 2xArH meta to OMe), 7.8-8.0 (1H, m, pyridine H ₅), 8.4-8.65 (2H, m,pyridine H) and 8.87 (1H, ˜d, J 2.0 Hz, pyridine H ₂).

[0356] The following compound was prepared in a manner similar to thecompound of Example 5a)

[0357] b) 4{-2-r4-Methoxy-3-(5-phenylpentyloxy)phenylethyl}pyridine

[0358] From the compound of Example 1c) (0.534 g, 1.43 mmol) and 5% Pd/Ccatalyst (40 mg). Chromatography (SiO₂; EtOAc-hexane, 3:1) gave a clearcolourless oil which solidified to give the title compound (0.45 g) as awhite amorphous solid. m.p. 59-62° C. (Found C, 79.63;H, 7.79; N, 3.57.C₂₅H₂₉NO₂ requires C, 79.96;H, 7.78; N, 3.73%) δ_(H) (300 MHz; CDCl₃)1.4-1.9 (6H, br m, (CH ₂)₃), 2.65 (2H, t, J 7.7 Hz, ArCH ₂), 2.83-2.91(4H, m, (CH ₂)₂), 3.83 (3H, s, OCH ₃), 3.94 (2H, t, J 6.8 Hz, OCH ₂),6.63 (1H, d, J 2.0 Hz, ArH ₂), 6.66 (1H, dd, J 8.0, 2.0 Hz, ArH ₆), 6.78(1H, d, J 8.1 Hz, ArH ₄), 7.06 (2H, dd, J 4.4, 1.6 Hz, pyridine H ₃, H₅), 7.15-7.3 (5H, m, ArH), and 8.47 (2H, dd, J 4.4, 1.6 Hz, pyridine H₂, H ₆).

[0359] c) 4-[2-(4-Methoxy-3-butylphenyl)-2-phenylethyl]pyridinehydrochloride

[0360] From the compound of Example 4d). Chromatography (SiO₂;EtOAc-hexane, 1:9) gave the title compound free base as a colourlessoil. The free base was treated with ethanolic HCl to give the titlecompound as an off-white solid. (Found C, 78.13;H, 6.98; N, 3.02C₃₀H₃₂NOCl requires C, 78.67;H, 7.04; N, 3.06%). δ_(H) (CDCl₃) 1.55 (4H,m, CH₂(CH ₂)CH₂), 2.60 (4H, m, CH ₂(CH₂)₂CH₂), 3.55 (2H, d, pyridine (CH₂), 3.75 (3H, s, OCH ₃), 4.15 (1H, t, ARCH), 6.70 (m, ArH), 6.90 (2H, m,ArH), 7.10-7.30 (10 H, m, 2xC₆ H ₅), 7.4 (2H, d, ArH) and 8.55 (2H, d,ArH).

EXAMPLE 6

[0361] Methyl 3-[Cyclopentylidenyl4methoxyphenyl]propenoate

[0362] A mixture of trimethylphosphonoacetate (2.7 g, 14.8 mmol) andIntermediate 13 (3.00 g, 13.9 mmol) in MeOH (30 ml) was added to asolution of sodium methoxide [prepared from sodium (0.4 g, 17.4 mmol) inMeOH (50 ml) at RT]. The reaction mixture was stirred at RT overnightthen the crystalline product collected by filtration, washed with MeOH(2×10 ml), and dried in vacuo to afford the title compound (2.70 g) as awhite solid (Found: C, 74.73;H, 7.43 C₁7H2003 requires: C, 74.97;H,7.40%); δ_(H) (80 MHz; CDCl₃) 1.5-1.8 (4H, br m, CH₂(CH₂)₂), 2.4-2.6(4H, br m, CH ₂(CH₂)₂CH ₂), 3.77 (3H, s, OMe), 6.25 (1H, d, J 15.8 Hz,CH═CH), 6.45-6.55 (1H, br m, CH═CCH₂), 6.80 (1H, d, J 8.7 Hz, ArH orthoto OMe), 7.28 (1H, dd, J 8.7, 2.6 Hz, ArH para to cyclopentylidene),7.48 (1H, d, J 2.6 Hz, ArH ortho to cyclopentylidene), and 7.61 (1H, d,J 15.8 Hz, CH═CH); m/z (El) 273 (M ⁺+1, 18%), 272 (100), 241 (11), 239(11), 225 (11), 205 (19), 192 (17), 175 (11), 161 (17), and 115 (18).

[0363] The activity and selectivity of compounds according to theinvention was demonstrated in the following tests. In these tests theabbreviation FMLP represents the peptide N-formyl-met-leu-phe.

[0364] 1. Isolated Enzyme

[0365] The potency and selectivity of the compounds o f the inventionwas i. PDE I, rabbit heart ii. PDE II, rabbit heart iii. PDE III, rabbitheart, Jurkat cells iv. PDE IV, HL60 cells, rabbit brain, rabbit kidneyand human recombinant PDE IV v. PDE V, rabbit lung, guinea pig lung

[0366] A gene encoding human PDE IV has been cloned from human monocytes(Livi, et al., 1990, Molecular and Cellular Biology, 10, 2676). Usingsimilar procedures we have cloned human PDE IV genes from a number ofsources including eosinophils, neutrophils, lymphocytes, monocytes,brain and neuronal tissues. These genes have been transfected into yeastusing an inducible vector and various recombinant proteins have beenexpressed which have the biochemical characteristics of PDE IV (Beavoand Reifsnyder, 1990, TIPS, 11, 150). These recombinant enzymes,particularly the human eosinophil recombinant PDE IV, have been used asthe basis of a screen for potent, selective PDE IV inhibitors.

[0367] The enzymes were purified to isoenzyme homogeneity using standardchromatographic techniques.

[0368] Phosphodiesterase activity was assayed as follows. The reactionwas conducted in 150 μl of standard mixture containing (finalconcentrations): 50 mM2—[[tris(hydroxymethyl)methyl]amino]-1-ethanesulphonic acid (TES)-NaOHbuffer (pH 7.5), 10 mM MgCl₂, 0.1 μM [³H]-cAMP and vehicle or variousconcentrations of the test compounds. The reaction was initiated byaddition of enzyme and conducted at 30° C. for between 5 to 30 min. Thereaction was terminated by addition of 50 μl 2% trifluoroacetic acidcontaining [¹⁴C]-5′AMP for determining recovery of the product. Analiquot of the sample was then applied to a column of neutral aluminaand the [³H]-cAMP eluted with 10 ml 0.1 TES—NaOH buffer (pH8). The[³H]-5′-AMP product was eluted with 2 ml 2M NaOH into a scintillationvial containing 10 ml of scintillation cocktail. Recovery of [3H]-5′AMPwas determined using the [¹⁴C]-5′AMP and all assays were conducted inthe linear range of the reaction.

[0369] Compounds according to the invention such as compounds of theExamples herein cause a concentration-dependent inhibition ofrecombinant PDE IV at 0.1-1000 nM with little or no activity against PDEI, II, III or V at concentrations up to 100 μM.

[0370] 2. The Elevation of CAMP in Leukocytes

[0371] The effect of compounds of the invention on intracellular cAMPwas investigated using human neutrophils or guinea pig eosinophils.

[0372] Human neutrophils were separated from peripheral blood, incubatedwith dihydrocytochalasin B and the test compound for 10 min and thenstimulated with FMLP. Guinea pig eosinophils were harvested byperitoneal lavage of animals previously treated with intra-peritonealinjections of human serum. Eosinophils were separated from theperitoneal exudate and incubated with isoprenaline and test compound.With both cell types, suspensions were centrifuged at the end of theincubation, the cell pellets were resuspended in buffer and boiled for10 min prior to measurement of cAMP by specific radioimmunoassay(DuPont).

[0373] The most potent compounds according to the Examples induced aconcentration -dependent elevation of cAMP in neutrophils and/oreosinophils at concentrations of 0.1nM to 1 μM.

[0374] 3. Suppression of Leukocyte Function

[0375] Compounds of the invention were investigated for their effects onsuperoxide generation, chemotaxis and adhesion of neutrophils andeosinophils. Isolated leukocytes were incubated withdihydrocyto-chalasin B for superoxide generation only and test compoundprior to stimulation with FMLP. The most potent compounds of theExamples caused a concentration-dependent inhibition of superoxidegeneration, chemotaxis and adhesion at concentrations of 0.1 nM to 1 μM.

[0376] Lipopolysaccharide (LPS)-induced synthesis of tumour necrosisfactor (TNF) by human peripheral blood monocytes (PBM) is inhibited bycompounds of the Examples at concentrations of 0.01 nM to 1 μM.

[0377] 4. Adverse Effects

[0378] In general, in our tests, compounds of the invention have had noobserved toxic effects when administered to animals at pharmacologicallyeffect doses.

1. A compound of formula (1)

wherein ═W— is (1) ═C(Y)— where Y is a halogen atom, or an alkyl or—XR^(a) group where X is —O—, —S(O)_(m)—[where m is zero or an integerof value 1 or 2], or —N(R^(b))— where R^(b) is a hydrogen atom or anoptionally substituted alkyl group] and R^(a) is a hydrogen atom or anoptionally substituted alkyl group or, (2) ═N—; L is (1) a—C(R)═C(R¹)(R²) or [—CH(R)]_(n)CH(Rl)(R²) group where R is a hydrogen ora fluorine atom or a methyl group, and R¹ and R², which may be the sameor different, is each a hydrogen or fluorine atom or an optionallysubstituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, —CO₂R⁸ [where R⁸is a hydrogen atom or an optionally substituted alkyl, aralkyl or arylgroup], —CONR⁹R¹⁰ [where R⁹ and R¹⁰, which may be the same or differentare defined for R⁸], —CSNR⁹R¹⁰,—CN or —NO₂ group, or R¹ and R², togetherwith the C atom to which they are attached are linked to form anoptionally substituted cycloalkyl, cycloalkenyl or heterocycloaliphaticgroup and n is zero or the integer 1; or is (2)—(X^(a))_(n)Alk′Ar′, or-Alk′X^(a)Ar′ where X^(a) is a group X, Ar′ is an optionally substitutedheterocycloaliphatic, or an optionally substituted monocylic or bicyclicaryl group optionally containing one or more heteroatoms selected fromoxygen, sulphur or nitrogen atoms, Alk′ is an optionally substitutedstraight or branched alkylene, alkenylene or alkynylene chain optionallyinterrupted by one or more L¹ atoms or groups [where L¹ is a linker atomor group] and n is zero or the integer 1; or is (3) X^(a)R′ where R′ Ar′or is an optionally substituted polycycloalkyl or polycycloalkenyl groupoptionally containing one or more —O—, or —S— atoms or —N(R^(b))—groups; Z is a group (A), (B), (C) or (D):

wherein Ar is a monocyclic or bicyclic aryl group optionally containingone or more heteroatoms selected from oxygen, sulphur or nitrogen atoms;Z′ is a group —NR¹²C(O)—[where R¹² is a hydrogen atom or an optionallysubstituted alkyl or (Alk)_(t)Ar group], —C(O)NR¹²—, —NR¹²C(S)—,—C(S)NR¹²—, —C≡C—, —NR¹²SO₂—, or —SO₂NR¹²—; Alk is an optionallysubstituted straight or branched alkyl chain optionally interrupted byan atom or group X; t is zero or an integer of value 1, 2 or 3; R³ is ahydrogen or a fluorine atom or an optionally substituted straight orbranched alkyl group or an OR¹¹ group (where R¹¹ is a hydrogen atom oran optionally substituted alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl,carboxamido or thiocarboxamido group]; R⁴ is a hydrogen atom or anoptionally substituted alkyl, —CO₂R8, —CSNR⁹R¹⁰, —CN, —CH₂CN, or—(CH₂)_(t)Ar group where t is zero or an integer of value 1, 2 or 3 andAr is a monocyclic or bicyclic aryl group optionally containing one ormore heteroatoms selected from oxygen, sulphur or nitrogen atoms,provided that when L is a group of type (2) or (3) above then Z is agroup of type (A) or type (B) in which R⁴ is a —(CH₂)_(t)Ar group; R⁵ isa group —(CH₂)_(t)Ar; R⁶ is a hydrogen or a fluorine atom, or anoptionally substituted alkyl or —CO₂R8, —CONR⁹R¹⁰, —CSNR⁹R¹⁰, —CN or—CH₂CN group; R⁷ is a hydrogen or a fluorine atom, an optionallysubstituted straight or branched alkyl group, or an OR^(c) group whereR^(c) is a hydrogen atom or an optionally substituted alkyl or alkenylgroup, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamidogroup; and the salts, solvates, hydrates, prodrugs and N-oxides thereof.2. A compound according to claim 1 wherein W is a ═C(XRa)— group.
 3. Acompound according to claim 2 wherein L is a —C(R)═C(R¹)(R²) group inwhich R¹ and R², together with the C atom to which they are attached arelinked to form a cycloalkyl group.
 4. A compound according to claim 1wherein Z is a group (A) or (B), in which R³, R⁶ and R⁷ is each ahydrogen atom, R⁴ is an aryl group and R⁵ is a heteroaryl group.
 5. Acompound according to claim 4 wherein R⁴ is an optionally substitutedphenyl group and R⁵ is an optionally substituted pyridyl group.
 6. Acompound which is:4-{2-[4-Methoxy-3-(phenylpentyloxy)phenyl]-2-phenylethyl}pyridine;4-[2-(4-Methoxy-3-(3-thienyloxy)phenyl)-2-phenylethyl]pyridine;4-{2-[3-(4-Biphenyloxy)-4-methoxyphenyl)-2-phenyl]ethyl}pyridine;4-[2-(3-((2RS)-exo-Bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl)-2-phenylethyl]pyridine;3-(3-Cyclopentylidenyl-4-methoxyphenyl)pyridine; the resolvedenantiomer; and the salts, solvates, hydrates, prodrugs and n-oxidesthereof
 7. A pharmaceutical composition comprising a compound of formula(1)

wherein ═W— is (1) ═C(Y)— where Y is a halogen atom, or an alkyl or—XR^(a) group where X is —O—, —S(O)_(m)—[where m is zero or an integerof value 1 or 2], or —N(R^(b))—[where R^(b) is a hydrogen atom or anoptionally substituted alkyl group] and R^(a) is a hydrogen atom or anoptionally substituted alkyl group or, (2) ═N—; L is (1) a—C(R)═C(R¹)(R²) or [—CH(R)]_(n)CH(R¹)(R²) group where R is a hydrogen ora fluorine atom or a methyl group, and R¹ and R², which may be the sameor different, is each a hydrogen or fluorine atom or an optionallysubstituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, —CO₂R⁸ [where R⁸is a hydrogen atom or an optionally substituted alkyl, aralkyl or arylgroup], —CONR⁹R¹⁰ [where R⁹ and R¹⁰, which may be the same or differentare defined for R⁸], —CSNR⁹R¹⁰,—CN or —NO₂ group, or R¹ and R², togetherwith the C atom to which they are attached are linked to form anoptionally substituted cycloalkyl, cycloalkenyl or heterocycloaliphaticgroup and n is zero or the integer 1; or is (2)—(X^(a))_(n)Alk′Ar′, or-Alk′X^(a)Ar′ where X^(a) is a group X, Ar′ is an optionally substitutedheterocycloaliphatic, or an optionally substituted monocylic or bicyclicaryl group optionally containing one or more heteroatoms selected fromoxygen, sulphur or nitrogen atoms, Alk′ is an optionally substitutedstraight or branched alkylene, alkenylene or alkynylene chain optionallyinterrupted by one or more L¹ atoms or groups [where L¹ is a linker atomor group] and n is zero or the integer 1; or is (3) X^(a)R′ where R′ isAr′ or is an optionally substituted polycycloalkyl or polycycloalkenylgroup optionally containing one or more —O—, or —S— atoms or —N(R^(b))—groups; Z is a group (A), (B), (C) or (D):

wherein Ar is a monocyclic or bicyclic aryl group optionally containingone or more heteroatoms selected from oxygen, sulphur or nitrogen atoms;Z¹ is a group —NR¹²C(O)—[where R¹² is a hydrogen atom or an optionallysubstituted alkyl or (Alk)_(t)Ar group], —C(O)NR¹²—, —NR¹²C(S)—,—C(S)NR¹²—, —C≡C—, —NR¹²SO₂—, or —SO₂NR¹²—; Alk is an optionallysubstituted straight or branched alkyl chain optionally interrupted byan atom or group X; t is zero or an integer of value 1, 2 or 3; R³ is ahydrogen or a fluorine atom or an optionally substituted straight orbranched alkyl group or an OR¹¹ group [where R¹¹ is a hydrogen atom oran optionally substituted alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl,carboxamido or thiocarboxamido group]; R⁴ is a hydrogen atom or anoptionally substituted alkyl, —CO₂R⁸, —CSNR⁹R¹⁰, —CN, —CH₂CN, or—(CH₂)_(t)Ar group where t is zero or an integer of value 1, 2 or 3 andAr is a monocyclic or bicyclic aryl group optionally containing one ormore heteroatoms selected from oxygen, sulphur or nitrogen atoms,provided that when L is a group of type (2) or (3) above then Z is agroup of type (A) or type (B) in which R⁴ is a —(CH₂)_(t)Ar group; R⁵ isa group —(CH₂)_(t)Ar; R⁶ is a hydrogen or a fluorine atom, or anoptionally substituted alkyl or —CO₂R⁸, —CONR⁹R¹⁰, —CSNR⁹R¹⁰, —CN or—CH₂CN group; R⁷ is a hydrogen or a fluorine atom, an optionallysubstituted straight or branched alkyl group, or an OR^(c) group whereR^(c) is a hydrogen atom or an optionally substituted alkyl or alkenylgroup, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamidogroup; and the salts, solvates, hydrates, prodrugs and N-oxides thereof;together with one or more pharmaceutically acceptable carriers,excipients or diluents.
 8. A process for the preparation of a compoundof formula (1)

wherein ═W— is (1) ═C(Y)— where Y is a halogen atom, or an alkyl or—XR^(a) group where X is —O—, —S(O)_(m)—[where m is zero or an integerof value 1 or 2], or —N(R^(b))—[where R^(b) is a hydrogen atom or anoptionally substituted alkyl group] and R^(a) is a hydrogen atom or anoptionally substituted alkyl group or, (2) ═N—; L is (1) a—C(R)═C(R¹)(R²) or [—CH(R)]_(n)CH(R¹)(R²) group where R is a hydrogen ora fluorine atom or a methyl group, and R¹ and R², which may be the sameor different, is each a hydrogen or fluorine atom or an optionallysubstituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, —C02R8 [where R8is a hydrogen atom or an optionally substituted alkyl, aralkyl or arylgroup], —CONR⁹R¹⁰ [where R⁹ and R¹⁰, which may be the same or differentare defined for R⁸], —CSNR⁹R¹⁰,—CN or —NO₂ group, or R¹ and R², togetherwith the C atom to which they are attached are linked to form anoptionally substituted cycloalkyl, cycloalkenyl or heterocycloaliphaticgroup and n is zero or the integer 1; or is (2)—(X^(a))_(n)Alk′Ar′, or-Alk′X^(a)Ar′ where X^(a) is a group X, Ar′ is an optionally substitutedheterocycloaliphatic, or an optionally substituted monocylic or bicyclicaryl group optionally containing one or more heteroatoms selected fromoxygen, sulphur or nitrogen atoms, Alk′ is an optionally substitutedstraight or branched alkylene, alkenylene or alkynylene chain optionallyinterrupted by one or more L¹ atoms or groups [where L¹ is a linker atomor group] and n is zero or the integer 1; or is (3) X^(a)R′ where R′ isAr′ or is an optionally substituted polycycloalkyl or polycycloalkenylgroup optionally containing one or more —O—, or —S— atoms or —N(R^(b))—groups; Z is a group (A), (B), (C) or (D):

wherein Ar is a monocyclic or bicyclic aryl group optionally containingone or more heteroatoms selected from oxygen, sulphur or nitrogen atoms;Z¹ is a group —NR¹²C(O)—[where R¹² is a hydrogen atom or an optionallysubstituted alkyl or (Alk)_(t)Ar group], —C(O)NR¹²—, —NR¹²C(S)—,—C(S)NR¹²—, —C≡C—, —NR¹²SO₂—, or —SO₂NR¹²—; Alk is an optionallysubstituted straight or branched alkyl chain optionally interrupted byan atom or group X; t is zero or an integer of value 1, 2 or 3; R³ is ahydrogen or a fluorine atom or an optionally substituted straight orbranched alkyl group or an OR¹¹ group [where R¹¹ is a hydrogen atom oran optionally substituted alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl,carboxamido or thiocarboxamido group]; R⁴ is a hydrogen atom or anoptionally substituted alkyl, —CO₂R⁸, —CSNR⁹R¹⁰, —CN, —CH₂CN, or—(CH₂)_(t)Ar group where t is zero or an integer of value 1, 2 or 3 andAr is a monocyclic or bicyclic aryl group optionally containing one ormore heteroatoms selected from oxygen, sulphur or nitrogen atoms,provided that when L is a group of type (2) or (3) above then Z is agroup of type (A) or type (B) in which R⁴ is a —(CH₂)_(t)Ar group; R⁵ isa group —(CH₂)_(t)Ar; R⁶ is a hydrogen or a fluorine atom, or anoptionally substituted alkyl or —CO₂R⁸, —CONR⁹R¹⁰, —CSNR⁹R¹, —CN or—CH₂CN group; R⁷ is a hydrogen or a fluorine atom, an optionallysubstituted straight or branched alkyl group, or an OR^(c) group whereR^(c) is a hydrogen atom or an optionally substituted alkyl or alkenylgroup, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamidogroup; and the salts, solvates, hydrates, prodrugs and N-oxides thereof;which comprises in a final step: a) coupling a compound of formula (3)

i) where L² is a group X^(a)H with a reagent L³Alk′Ar′, or L³R′ in whichL³ is a leaving group; or ii) where L² is a group -Alk′L³ with a reagentAr′X^(a)H; b) reacting a compound of formula (12)

 where R⁴ is a hydrogen atom, or an alkyl or —(CH₂)_(t)Ar group with aphosphonate ester to give a compound of formula (1) wherein Z is a group(B); c) coupling a compound of formula (18)

 with an organopalladium compound to give a compound of formula (1)wherein Z is a group (B); d) reacting a compound of formula (19)

 with an organometallic reagent followed by dehydration of thecorresponding alcohol to give a compound of formula (1) wherein L is agroup —C(R)═CH(R¹); e) decarboxylating an acid of formula (21)

 to give a compound of formula (1) wherein R³, R⁶ and R⁷ is each ahydrogen atom; f) cyclisation of a compound of formula (23)

 where R¹⁶ is a carboxylic acid (CO₂H) or a reactive derivative thereof;or a nitrile (-CN) or an imine salt with a bifunctional reagentW¹R^(5a)W² and, where necessary, a compound R^(5b)W³ [where W¹, W² andW³, which may be the same or different, is each a reactive functionalgroup or a protected derivative thereof; and R^(5a) and R^(5b)arecomponents of the heteroaryl group R⁵ such that when added together withWI, W² and W³ to the group R¹⁶ in compounds of formula (19) theresulting group —RW¹R^(5a)W² or —RW¹R^(5a)W²R^(5b)W³ constitutes theheteroaryl group R⁵]; to give a compound of formula (1) wherein R³, R⁶and R⁷ is each a hydrogen atom and R⁵ is a heteroaryl group to give acompound of formula (1) wherein R³, R⁶ and R⁷ is each a hydrogen atomand R⁵ is a heteroaryl group; g) coupling a compound of formula (25)

 where E is a boronic acid —B(OH)₂ or a tin reagent Sn(R)₃, in which Ris an alkyl group with a reagent Z-L⁴, where L⁴ is a leaving group, inthe presence of a complex metal catalyst; to give a compound of formula(1) wherein Z is a group (C); h) coupling a compound of formula (26)

 where A is a —CO₂H or —NHR¹² group, or an active derivative thereofwith a compound R¹²NH(Alk_(t)(Xn)Ar or Ar(X)_(n)Alk)_(t)CO₂H or anactive derivative thereof to give a compound of formula (1) wherein Z isa group (D) in which —Z¹ is —NR¹²C(O)— or —C(O)NR¹²—; i) reacting acompound of formula (29)

 with a reagent Ar(X)_(n)(Alk)_(t)L⁵ in which L⁵ is a leaving group togive a compound of formula (1) wherein Z¹ is a —C═C-chain; j) reacting acompound of formula (30)

 where (i) W^(b) is a —NHR¹² group with a compoundAr(X)_(n)(Alk)_(t)SO₂Hal (where Hal is a halogen atom); or  (ii) W^(b)is a —SO₂Hal group with a compound Ar(X)_(n)(Alk)_(t)NHR¹² to give acompound of formula (1) wherein Z¹ is a —NR¹²SO₂— or —SO₂NR¹²— group; k)reacting a compound of formula (31)

 where Hall is a halogen atom  where a diazoalkane to give a compound offormula (1) where L is a —CH(R¹)(R²)group in which R² is a —CO₂H group;or l) interconverting a compound of formula (1) to another compound offormula (1).